Tracking APL progress with RT-PCR Testing
Testing disease status helps to predict relapse and potentially improve outcomes for acute
promyelocytic leukemia (APL) patients.
1-4
One method of assessing APL status is reverse transcriptase-polymerase chain reaction testing, or RT-PCR
testing. RT-PCR testing presents the opportunity to detect impending relapse rather than wait
for signs of clinical relapse. Based on a review of the literature, Tallman and colleagues
concluded that a reasonable schedule of testing is to obtain at least two successive marrow
samples at the end of treatment performed every three months for the first two years of CR and
then every six months for the next two to three years.
1
Genetic testing can help track disease status, predict relapse, and improve outcomes.
RT-PCR testing analyzes the chromosome abnormalities that define APL specifically. APL is usually
marked by a translocation of genes between chromosomes 15 and 17, represented as t(15;17).
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Part of the PML (promyelocytic leukemia) gene transfers to chromosome 17 and part of the RAR-alpha
(retinoic acid receptor-alpha) gene transfers to chromosome 15. The result is a fusion protein
product with characteristics of both the PML gene and the RAR-alpha receptor protein.
5-8
Expression of the fusion produced by the translocation of genes between chromosomes 15 and 17 is
detected with the RT-PCR test, which offers the following two benefits:
1. The test is predictive of relapse and survival.
A positive PML/RAR-alpha test after consolidation therapy reliably predicts subsequent hematologic
relapse, whereas repeatedly negative results are associated with long-term survival in the
majority of patients.
1 In one study, 163 patients were induced into remission by ATRA
combined with chemotherapy, and were tested at regular intervals after the end of treatment.
Twenty of the 21 patients who converted to a positive PCR relapsed within a median of 3 months,
whereas the 3-year estimate of relapse risk of patients who tested negative at least twice after
consolidation was less than 10%.
2
2. Test results can guide therapy, leading to improved patient outcomes.
Patients who convert to a positive PCR can be salvaged early with chemotherapy prior to overt
disease.
1,3 This results in a significantly improved outcome compared to delaying
treatment until morphologic evidence of relapse. It is anticipated that therapy at the time of
molecular relapse will be associated with a lower mortality rate than that observed with
reinduction of overt disease.
1,3 In one study, 14 APL patients were prospectively
monitored after consolidation therapy with the AIDA protocol (all-trans retinoic acid [ATRA]
plus idarubicin). Patients were treated at the time of molecular relapse (defined as two
successive RT-PCR positive samples), rather than at clinical relapse. Early treatment for
relapse with 30 days of oral ATRA followed by four daily courses of chemotherapy with
cytarabine and mitoxantrone resulted in achievement of a second molecular remission in 12
patients (86%).
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>> Click here to review how TRISENOX may work to achieve
remission for your relapsed or refractory APL patients.
TRISENOX is indicated for induction of remission and consolidation in patients with APL who
are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose
APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
Serious adverse events, grade 3 or 4, were common. Those events attributable to TRISENOX in the Phase 2
study of 40 patients with refractory or relapsed APL included APL differentiation syndrome (n=3), hyperleukocytosis (n=3), QTc
interval prolongation (n=16), atrial dysrhythmias (n=2), hyperglycemia (n=2), and torsades de pointes (n=1).
In addition to QT interval prolongation, the most common drug-related side effects included leukocytosis, gastrointestinal events (nausea, vomiting, diarrhea, and abdominal pain), fatigue, swelling, hyperglycemia (an abnormal increased content of sugar in the blood), shortness of breath, cough, rash or itching, headache, and dizziness. Have your doctor review side effects with you.
In clinical trials, most patients taking TRISENOX experienced some drug-related toxicity, most commonly leukocytosis, gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headache, and dizziness. These adverse effects have not been observed to be permanent or irreversible, nor do they usually require interruption of therapy.
To report an adverse event contact Cephalon Medical Services at 1-800-896-5855 or usmedinfo@cephalon.com.
WARNING
Experienced Physician and Institution:
TRISENOX® (arsenic trioxide) injection should be administered under the supervision
of a physician who is experienced in the management of patients with acute leukemia.
APL Differentiation Syndrome:
Some patients with APL treated with TRISENOX have experienced symptoms similar to a syndrome called
the retinoic-acid-acute promyelocytic leukemia (RA-APL) or APL differentiation syndrome, characterized
by fever, dyspnea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or
without leukocytosis. This syndrome can be fatal. The management of the syndrome has not been fully
studied, but high-dose steroids have been used at the first suspicion of the APL differentiation
syndrome and appear to mitigate signs and symptoms. At the first signs that could suggest the syndrome
(unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic
abnormalities), high-dose steroids (dexamethasone 10 mg intravenously BID) should be immediately
initiated, irrespective of the leukocyte count, and continued for at least 3 days or longer until
signs and symptoms have abated. The majority of patients do not require termination of TRISENOX therapy
during treatment of the APL differentiation syndrome.
ECG Abnormalities:
Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT prolongation can
lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes
is related to the extent of QT prolongation, concomitant administration of QT prolonging drugs, a history of
torsade de pointes, pre-existing QT interval prolongation, congestive heart failure, administration of
potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia. One patient
(also receiving amphotericin B) had torsade de pointes during induction therapy for relapsed APL with arsenic
trioxide.
ECG and Electrolyte Monitoring Recommendations:
Prior to initiating therapy with TRISENOX, a 12-lead ECG should be performed and serum electrolytes (potassium,
calcium, and magnesium) and creatinine should be assessed; pre-existing electrolyte abnormalities should be
corrected and, if possible, drugs that are known to prolong the QT interval should be discontinued. For QTc
greater than 500 msec, corrective measures should be completed and the QTc reassessed with serial ECGs prior
to considering using TRISENOX. During therapy with TRISENOX, potassium concentrations should be kept above 4 mEq/L
and magnesium concentrations should be kept above 1.8 mg/dL. Patients who reach an absolute QT interval value > 500
msec should be reassessed and immediate action should be taken to correct concomitant risk factors, if any, while
the risk/benefit of continuing versus suspending TRISENOX therapy should be considered. If syncope, rapid or irregular
heartbeat develops, the patient should be hospitalized for monitoring, serum electrolytes should be assessed, TRISENOX
therapy should be temporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte abnormalities
are corrected, and the syncope and irregular heartbeat cease. There are no data on the effect of TRISENOX on the QTc
interval during the infusion.
1. Lowenberg B, Griffin JD, Tallman MS. Acute myeloid leukemia and acute promyelocytic leukemia. Hematology Am Soc Hematol Educ Program. 2003;82-101.
2. Diverio D, Rossi V, Avvisati G. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RAR alpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter "AIDA" trial. GIMEMA-AIEOP Multicenter "AIDA" Trial. Blood. 1998;92:784-789.
3. Lo Coco F, Diverio D, Avvisati G, et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood. 1999;94:2225-2229.
4. Lo Coco F, Diverio D, Falini B. Genetic diagnosis and molecular monitoring in the management of acute promyelocytic leukemia. Blood. 1999;94:12-22.
5. Grignani F, Fagioli M, Alcalay M, et al. Acute promyelocytic leukemia: from genetics to treatment. Blood. 1994;83:10-25.
6. Douer D, Tallman MS. Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies. J Clin Oncol. 2005;23:2396-2410.
7. Miller WH Jr, Schipper HM, Lee JS, et al. Mechanisms of action of arsenic trioxide. Cancer Res. 2002;62:3893-3903.
8. Davison K, Mann KK, Miller WH Jr. Arsenic trioxide: mechanisms of action. Semin Hematol. 2002;39(2 Suppl 1):3-7.