Treatment Options Under Clinical Evaluation
Current Clinical Trials

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) and is treated differently than other types of AML. Optimal treatment requires rapid initiation of treatment and supportive care measures.[1] The characteristic chromosomal abnormality associated with APL is t(15;17). This translocation involves a breakpoint that includes the retinoid acid receptor and that leads to production of the promyelocytic leukemia/retinoic acid receptor alpha (PML/RARA) fusion protein.[2]

Clinically, APL is commonly characterized by a severe coagulopathy often present at the time of diagnosis.[3] Mortality during induction (with cytotoxic agents) due to bleeding complications is more common in this subtype than other French-American-British classifications. Because of the extremely low incidence of central nervous system disease in patients with APL, a lumbar puncture is not required at the time of diagnosis and prophylactic intrathecal chemotherapy is not administered. Studies have demonstrated that the absence of PML/RARA RNA chimeric transcript expression at the end of therapy, as detected by reverse-transcription–polymerase chain reaction monitoring, predicts a low risk of relapse.[4-6]

The leukemia cells from patients with APL are especially sensitive to the differentiation-inducing effects of all-trans retinoic acid (ATRA). The basis for the dramatic efficacy of ATRA. against APL is the ability of pharmacologic doses of ATRA to overcome the repression of signaling caused by the PML/RARA fusion protein at physiologic ATRA concentrations. Restoration of signaling leads to differentiation of APL cells and then to postmaturation apoptosis.[7] Most patients with APL achieve a complete remission (CR) when treated with ATRA, though single-agent ATRA is generally not curative.[8,9] A series of randomized clinical trials has defined the benefit for combining ATRA with chemotherapy during induction therapy and also the utility of using ATRA as maintenance therapy.[10-12] For children with APL, survival rates exceeding 80% are now achievable.[13-15]

Molecular variants of APL produce fusion proteins that join distinctive gene partners (e.g., PLZF, NPM, STAT5B, and NuMA) to RARA.[16] Recognition of these rare variants is important as they differ in their sensitivity to ATRA and to arsenic trioxide.[17] The PLZF-RARA variant, characterized by t(11;17)(q23q21), represents about 0.8% of APL, expresses surface CD56 and has very fine granules compared to t(15;17) APL.[18-20] APL with PLZF-RARA has been associated with a poor prognosis and does not respond to ATRA or to arsenic trioxide.[17-20] The rare APL variants with NPM-RARA [t(5;17)(q35,q21)] or with NuMA-RARA [t(11;17)(q13,q21)] translocations are responsive to ATRA.[17,21-24]

APL in children is generally similar to APL in adults, though children have a higher incidence of hyperleukocytosis (defined as white blood cell [WBC] count greater than 10 x 10⁹/L) and a higher incidence of the microgranular morphologic subtype.[13-15,25] Similar to adults, children with WBC count less than 10 x 10⁹/L at diagnosis have significantly better outcome than patients with higher WBC count.[14,15,26] FLT3 mutations (either internal tandem duplications or kinase domain mutations) are observed in 40% to 50% of APL cases, with presence of FLT3 mutations correlating with higher WBC counts and with the microgranular (M3v) subtype.[27-30] While some reports describe an association of FLT3 mutation with increased risk of treatment failure, this is not a consistent finding.[27-30]

The standard North American approach to treating children with APL utilizes induction therapy with ATRA, and standard-dose cytarabine and daunorubicin, followed by consolidation therapy with ATRA and daunorubicin.[31] Maintenance therapy, includes ATRA plus 6-mercaptopurine and methotrexate; this combination showed an advantage over ATRA alone in randomized trials in adults.[10,32] European clinical trials groups (Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto–Associazione Italiana Ematologia ed Ocologia Pediatrica [GIMEMA–AIEOP] and Programa de Estudio y Tratamiento de las Hemopatias Malignas [PETHEMA]) have utilized idarubicin and ATRA without cytarabine for remission induction for children with APL.[14,15] Subsequent therapies for these groups include treatment courses with an anthracycline (idarubicin and mitoxantrone) plus ATRA (PETHEMA) or treatment courses with an anthracycline, ATRA, and other agents (GIMEMA-AIEOP), with both groups utilizing maintenance therapy as described above.[14,15] Because of the positive results of the use of chemotherapy plus ATRA, hematopoietic stem cell transplatation is not recommended in first CR, but only following relapse and achievement of a second CR.

Arsenic trioxide has also been identified as an active agent in patients with APL. Approximately 85% of patients in relapse achieve morphologic remission following treatment with this agent in relapse.[33-37] Arsenic trioxide is well tolerated in children with relapsed APL. The toxicity profile and response rates in children are similar to that observed in adults.[37] In adults with newly diagnosed APL, the addition of two consolidation courses of arsenic trioxide to a standard APL treatment regimen resulted in a significant improvement in EFS and OS.[31] The combination of arsenic trioxide and ATRA may be particularly beneficial. In one study of adults and older children (older than or equal to 14 years) with newly diagnosed APL, patients were randomized to induction with ATRA alone, arsenic trioxide alone, or a combination of the two, followed by consolidation and maintenance. While the complete remission rate was high (greater than 90%) in all 3 groups, the combination group demonstrated greater reduction of PML/RAR alpha transcripts at remission and better DFS (100% of 20 patients) with a median followup of 18 months.[36] Because arsenic trioxide causes Q-T interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes),[38] it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.[39]

The following is an example of a national and/or institutional clinical trial that is currently being conducted. For more information about clinical trials, please see the NCI Web site.

• The COG will be conducting a study, AAML0631, evaluating the addition of two courses of arsenic trioxide plus ATRA to a backbone treatment regimen based on the Italian “AIDA” treatment regimen, [40] but with modifications to reduce the cumulative doses of anthracyclines. The primary objective is to decrease the total anthracycline dose from that used in regimens with the best current published results while still maintaining a comparable EFS. Promising results from pilot studies using arsenic trioxide and ATRA in newly diagnosed patients with APL also support evaluation of this combination.[41,42]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood acute promyelocytic leukemia (M3). The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

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