Childhood Acute Myeloid Leukemia Treatment (Professional) (cont.)
Acute Promyelocytic Leukemia
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 with all-trans retinoic acid (ATRA) and supportive care measures.[1,2] The characteristic chromosomal abnormality associated with APL is t(15;17). This translocation involves a breakpoint that includes the retinoic acid receptor and leads to production of the promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) fusion protein. Patients with a suspected diagnosis of APL can have their diagnosis confirmed by detection of the PML-RARA fusion (e.g., through fluorescence in situ hybridization [FISH], reverse transcriptase–polymerase chain reaction [RT–PCR], or conventional cytogenetics). An immunofluorescence method using an anti-PML monoclonal antibody can rapidly establish the presence of the PML-RARA fusion protein based on the characteristic distribution pattern of PML that occurs in the presence of the fusion protein.[4,5,6]
Clinically, APL is characterized by a severe coagulopathy that is often present at the time of diagnosis. Mortality during induction (particularly with cytotoxic agents used alone) due to bleeding complications is more common in this subtype than in other French-American-British classifications. A lumbar puncture at diagnosis should not be performed until evidence of coagulopathy has resolved.
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 higher than 10 × 109 /L) and a higher incidence of the microgranular morphologic subtype.[8,9,10,11] Similar to adults, children with WBC counts less than 10 × 109 /L at diagnosis have significantly better outcome than patients with higher WBC counts.[9,10,12] The prognostic significance of WBC count is used in defining high-risk and low-risk patient populations for assigning postinduction treatment, with high-risk patients most commonly defined by WBC of 10 × 109 /L or greater.[13,14]FLT3 mutations (either internal tandem duplications or kinase domain mutations) are observed in 40% to 50% of APL cases, with the presence of FLT3 mutations correlating with higher WBC counts and the microgranular (M3v) subtype.[15,16,17,18,19] While some reports describe an association of FLT3 mutation with increased risk of treatment failure, this has not been a consistent finding.[15,16,17,18,19]
The basis for current treatment programs for APL is the sensitivity of leukemia cells from patients with APL to the differentiation-inducing effects of ATRA. The dramatic efficacy of ATRA against APL results from 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. Most patients with APL achieve a complete remission (CR) when treated with ATRA, though single-agent ATRA is generally not curative.[21,22] A series of randomized clinical trials has defined the benefit of combining ATRA with chemotherapy during induction therapy and also the utility of using ATRA as maintenance therapy.[23,24,25] ATRA is also commonly used as a component of postinduction consolidation therapy, with treatment regimens that include several additional courses of ATRA given with an anthracycline with or without cytarabine.[10,13,14,26] Evidence for the benefit of giving ATRA with consolidation chemotherapy is derived from historical comparisons of results from adult APL clinical trials showing significant improvements in outcome for patients receiving ATRA given in conjunction with chemotherapy compared with chemotherapy alone.[13,14] For children with APL, survival rates exceeding 80% are now achievable using treatment programs that prescribe the rapid initiation of ATRA and appropriate supportive care measures.[1,8,9,10,13,14,26]
The standard approach to treating children with APL builds upon adult clinical trial results and begins with induction therapy using ATRA given in combination with an anthracycline administered with or without cytarabine. One regimen uses ATRA in conjunction with standard-dose cytarabine and daunorubicin,[8,27] while another utilizes idarubicin and ATRA without cytarabine for remission induction.[9,10] Almost all children with APL treated with one of these approaches achieves CR in the absence of coagulopathy-related mortality.[9,10,26,27] Assessment of response to induction therapy in the first month of treatment using morphologic and molecular criteria may provide misleading results as delayed persistence of differentiating leukemia cells can occur in patients who will ultimately achieve CR.[1,2] Alterations in planned treatment based on these early observations are not appropriate as resistance of APL to ATRA plus anthracycline-containing regimens is extremely rare.[14,28]
Consolidation therapy typically includes ATRA given with an anthracycline with or without cytarabine. The role of cytarabine in consolidation therapy regimens is controversial. While a randomized study addressing the contribution of cytarabine to a daunorubicin plus ATRA regimen in adults with low-risk APL showed a benefit for the addition of cytarabine, regimens using high-dose anthracycline appear to produce as good or better results for low-risk patients. For high-risk patients (WBC =10 × 109 /L), a historical comparison of the LPA2005 trial to the preceding PETHEMA LPA99 trial suggested that the addition of cytarabine to anthracycline-ATRA combinations can lower the relapse rate. The results of the AIDA-2000 trial confirmed that the cumulative incidence of relapse for adult patients with high-risk disease can be reduced to approximately 10% with consolidation regimens containing ATRA, anthracyclines, and cytarabine.
Maintenance therapy includes ATRA plus 6-mercaptopurine and methotrexate; this combination showed an advantage over ATRA alone in randomized trials in adults with APL.[23,31] A randomized study in adults has reported that maintenance therapy does not improve event-free survival (EFS) for patients with APL who achieve a complete molecular remission at the end of consolidation. The utility of maintenance therapy in APL may be dependent on multiple factors (e.g., risk group, the anthracycline used during induction, the intensity of induction and consolidation therapy, etc.), and at this time maintenance therapy remains standard for children with APL. Because of the favorable outcomes observed with chemotherapy plus ATRA (EFS rates of 70%–80%), hematopoietic stem cell transplantation (HSCT) is not recommended in first CR.
Central nervous system (CNS) relapse is uncommon for patients with APL, particularly for those with WBC less than 10 × 109 /L.[33,34] In two clinical trials enrolling over 1,400 adults with APL in which CNS prophylaxis was not administered, the cumulative incidence of CNS relapse was less than 1% for patients with WBC less than 10 × 109 /L, while it was approximately 5% for those with WBC of 10 × 109 /L or greater.[33,34] In addition to high WBC at diagnosis, CNS hemorrhage during induction is also a risk factor for CNS relapse. A review of published cases of pediatric APL also observed low rates of CNS relapse. Because of the low incidence of CNS relapse among children with APL presenting with WBC less than 10 × 109 /L, CNS surveillance and prophylactic CNS therapy may not be needed for this group of patients, although there is not consensus on this topic.
Arsenic trioxide has also been identified as an active agent in patients with APL, and there are now data for its use as induction therapy, consolidation therapy, and retrieval therapy:
- For adults with relapsed APL, approximately 85% achieve morphologic remission following treatment with this agent.[37,38,39] 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.
- 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 (80% vs. 63% at 3 years, P < .0001) and disease-free survival (90% vs. 70% at 3 years, P < .0001), although the outcome of patients who did not receive arsenic trioxide was inferior to the results obtained in the GIMEMA or PETHEMA trials. The Children's Oncology Group is evaluating arsenic trioxide as a consolidation therapy for newly diagnosed children with APL.
- The concurrent use of arsenic trioxide and ATRA in newly diagnosed patients with APL results in high rates of CR.[42,43,44] Early experience in children with newly diagnosed APL also shows high rates of CR to arsenic trioxide, either as a single agent or given with ATRA.[45,46] These results indicate that arsenic as a single agent or the combination of ATRA and arsenic are effective remission-induction regimens in both adult and pediatric patients, although the role of arsenic in terms of long-term EFS and OS is unclear and will require larger randomized studies.
Because arsenic trioxide causes QT interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes), it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.
The induction and consolidation therapies currently employed result in molecular remission as measured by reverse transcriptase–polymerase chain reaction (RT–PCR) for PML-RARA in the large majority of APL patients, with 1% or fewer showing molecular evidence of disease at the end of consolidation therapy.[14,28] While two negative RT-PCR assays after completion of therapy are associated with long-term remission, conversion from negative to RT-PCR positivity is highly predictive of subsequent hematologic relapse. Patients with persistent or relapsing disease based upon PML-RARA RT-PCR measurement may benefit from intervention with relapse therapies (refer to the Recurrent Acute Promyelocytic Leukemia (APL) subsection of the Recurrent Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies section of this summary for more information).
Molecular Variants of APL Other than PML-RARA
Uncommon molecular variants of APL produce fusion proteins that join distinctive gene partners (e.g., PLZF, NPM, STAT5B, and NuMA) to RARA. Recognition of these rare variants is important as they differ in their sensitivity to ATRA and to arsenic trioxide. 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 with t(15;17) APL.[53,54,55] APL with PLZF-RARA has been associated with a poor prognosis and does not usually respond to ATRA or to arsenic trioxide.[52,53,54,55] 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.[52,56,57,58,59]
Treatment Options Under Clinical Evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about clinical trials is available from the NCI Web site.
- COG-AAML0631(Combination Chemotherapy in Treating Young Patients With Newly Diagnosed APL): The Children's Oncology Group is conducting a study evaluating the addition of two courses of arsenic trioxide plus ATRA to a backbone treatment regimen based on the Italian AIDA treatment regimen, 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.[42,43,44]
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.
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