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. 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 PML/RARA fusion protein.[1]

Clinically, APL is commonly characterized by a severe coagulopathy often present at the time of diagnosis.[2] Mortality during induction 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.[3-5]

Some molecular variants are generally believed to be resistant to treatment with all-trans retinoic acid (ATRA). One such variant, characterized by t(11;17), represents about 0.8% of APL, expresses surface CD56 and has very fine granules compared to t(15;17) APL.[6-8] The t(11;17) variant has been associated with a poor prognosis. Although intensive multiagent chemotherapy regimens are usually used, novel approaches to therapy are needed for this rare but poor-prognosis subgroup of patients. Of interest, though believed to be refractory to ATRA, remissions have been achieved in these patients using ATRA plus granulocyte-macrophage colony-stimulating factor or ATRA plus chemotherapy.[9]

The leukemia cells from patients with APL are especially sensitive to the differentiation-inducing effects of 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.[10] Most patients with APL achieve a complete remission (CR) when treated with ATRA, though single-agent ATRA is generally not curative.[11,12] A series of randomized clinical trials have defined the benefit for combining ATRA with chemotherapy during induction therapy and also the utility of using ATRA as maintenance therapy.[13-15] For children with APL, survival rates exceeding 80% are now achievable.[16-18]

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.[16-19] 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.[17,18,20] The 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 (CALGB-C9710). Maintenance therapy, especially for high-risk patients, includes ATRA plus 6-mercaptopurine and methotrexate; this combination showed an advantage over ATRA alone in randomized trials in adults.[13,21] 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.[17,18] 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.[17,18] 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 with approximately 85% of patients achieving remission following treatment with this agent in relapse.[22-25] Data are limited on the use of arsenic trioxide in children, though published reports suggest that children with relapsed APL have a response to arsenic trioxide similar to that of adults.[22,24,26,27] A recent study in China randomized adults and older children (14 years or older) with newly diagnosed APL to induction with ATRA alone, arsenic trioxide alone, or a combination of the two, followed by consolidation and maintenance. While the CR rate was high (>90%) in all three groups, the combination group demonstrated greater reduction of PML/RARA transcripts at CR and better disease-free survival (100% of 20 patients) with a median follow-up of 18 months.[25] Although based on relatively small numbers of patients, these preliminary results are intriguing and may serve as the basis for future investigation with arsenic trioxide and ATRA combinations in trials for patients with newly diagnosed APL.[28] Because arsenic trioxide causes Q-T interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes),[29] it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.[30]

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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17. Testi AM, Biondi A, Lo Coco F, et al.: GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood 106 (2): 447-53, 2005.  [PUBMED Abstract]
    
    
18. Ortega JJ, Madero L, Martín G, et al.: Treatment with all-trans retinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: a multicenter study by the PETHEMA Group. J Clin Oncol 23 (30): 7632-40, 2005.  [PUBMED Abstract]
    
    
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