Current therapies in APL
Due to advancements in therapies, acute promyelocytic leukemia (APL) is considered
the most curable subtype of acute myeloid leukemia (AML).
1 Standard therapy
for APL is generally a form of vitamin A known as
all-trans
retinoic acid (ATRA), combined with an
anthracycline
(a member of a family of chemotherapy drugs that are also antibiotics). With this
treatment, 70% to 80% of patients with newly diagnosed APL achieve long-term remission
and are probably cured.
1
However, despite improvements in therapy, approximately one quarter of these patients
relapse and are often resistant to further treatment with ATRA.
1-3
Second-round therapies used to involve high doses of chemotherapy, which was often
toxic and rarely led to a cure.
Bone marrow transplantation may
be successful in achieving a cure, but it is an option for only a fraction of the
younger relapsed patients.
3
Clinical studies of
arsenic trioxide have demonstrated high
rates of complete remission for these patients, meaning there is no evidence of
disease, following treatment.
4,5 According to the National Comprehensive
Cancer Network (NCCN) guidelines for oncology, arsenic trioxide is the standard
of care for patients who have relapsed from, or did not respond to, their initial
treatment.
6
Types of APL treatment
ATRA
All-
trans retinoic acid (ATRA) is a non-chemotherapy drug that targets leukemia
cells. It is a relative of vitamin A. Although remission induction may be possible
with ATRA alone, combining ATRA with chemotherapy (with an anthracycline) has been
shown to achieve long-term remission and probably even a cure in 70% to 80% of patients
with newly diagnosed APL.
1
Chemotherapy
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer
cells, either by killing the cells or by stopping the cells from dividing. Anthracycline
is a member of a family of chemotherapy drugs that are also antibiotics. The anthracyclines
act to prevent cell division by disrupting the structure of the DNA and terminate
its function. Daunorubicin and idarubicin are two commonly used anthracyclines shown
to induce complete remission in 60% to 80% of APL patients.
7-9
Stem cell transplant
Stem cell transplant is a method of giving chemotherapy and replacing blood-forming
cells that are abnormal or destroyed by the cancer treatment. Stem cells (immature
blood cells) are removed from the blood or bone marrow of the patient or a donor
and are frozen and stored. After the chemotherapy is completed, the stored stem
cells are thawed and given back to the patient through an infusion. These reinfused
stem cells grow into, and restore, the body's blood cells.
Arsenic trioxide
Arsenic trioxide is the standard of care for APL patients whose disease returns
after or does not respond to initial treatment. Arsenic trioxide may be able to
kill leukemia cells, stop the leukemia cells from dividing, or help the leukemia
cells mature into white blood cells.
10-15
>> Click here to learn more about therapy
with TRISENOX including related safety information and full BOXED WARNING.
Phases of treatment
Usage of the above types of therapy depends on the treatment phase. APL patients
generally undergo three phases of treatment:
Induction therapy
This treatment is designed to be used as a first step toward shrinking the cancer
and in evaluating response to drugs and other agents. For APL patients, induction
therapy typically consists of ATRA with chemotherapy.
1 Induction therapy
is followed by additional therapy to eliminate whatever cancer remains.
Consolidation therapy
The purpose of this phase is to seek out and kill the residual leukemia cells not
killed by induction therapy. Often, these cells are not detectable, but they are
assumed to be present. This phase of treatment often involves high-dose chemotherapy.
Consolidation therapy is also called intensification therapy.
Maintenance therapy
This therapy is often given to help keep cancer in remission. The purpose of maintenance
therapy is to kill any remaining leukemia cells that may not be active but could
begin to regrow and cause a relapse. The doses of chemotherapy are not as high in
this phase as in the first two phases. It appears that APL patients benefit from
maintenance ATRA with or without continuous low-dose chemotherapy.
7 This
combination appears to be associated with the lowest relapse rate.
7
In between stages of therapy, testing such as reverse
transcriptase-polymerase chain reaction testing (RT-PCR testing) may be
performed to assess disease status.
>> Click here to learn more.
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.
It is important to call your doctor if you experience any treatment side effects.
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. Lengfelder E, Saussele S, Weisser A, et al. Treatment concepts of acute promyelocytic
leukemia. Crit Rev Oncol Hematol. 2005;56:261-274.
2. Douer D. Advances in the treatment of relapsed acute promyelocytic leukemia.
Acta Haematol. 2002;107:1-17.
3. Soignet SL. Clinical experience of arsenic trioxide in relapsed acute promyelocytic
leukemia. Oncologist. 2001;6 Suppl 2:11-16.
4. Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic
trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852-3860.
5. Soignet SL, Maslak P, Wang Z-G, et al. Complete remission after treatment of
acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998;339:1341-1348.
6. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology:
Acute Myeloid Leukemia — v.2.2009.
7. Lowenberg B, Griffin JD, Tallman MS. Acute myeloid leukemia and acute promyelocytic
leukemia. Hematology Am Soc Hematol Educ Program. 2003:82-101.
8. Bernard J, Weil M, Boiron M, et al. Acute promyelocytic leukemia: results of
treatment by daunorubicin. Blood. 1973;41:489-496.
9. Avvisati G, Mandelli F, Petti MC, et al. Idarubicin (4-demethoxydaunorubicin)
as single agent for remission induction of previously untreated acute promyelocytic
leukemia: a pilot study of the Italian cooperate group GIMEMA. Eur J Haematol.
1990;44:257-260.
10. Grignani F, Fagioli M, Alcalay M, et al. Acute promyelocytic leukemia: from
genetics to treatment. Blood. 1994;83:10-25.
11. Douer D, Tallman MS. Arsenic trioxide: new clinical experience with an old medication
in hematologic malignancies. J Clin Oncol. 2005;23:2396-2410.
12. Davison K, Mann KK, Miller WH Jr. Arsenic trioxide: mechanisms of action. Semin
Hematol. 2002;39(2 Suppl 1):3-7.
13. Miller WH Jr. Molecular targets of arsenic trioxide in malignant cells. Oncologist.
2002;7Suppl 1:14-19.
14. Hayakawa F, Privalsky ML. Phosphorlyation of PML by mitogen-activated protein
kinases plays a key role in arsenic trioxide-mediated apoptosis. Cancer Cell.
2004;5:389-401.
15. Mann KK, Miller WH Jr. Death by arsenic: implications of PML sumoylation. Cancer
Cell. 2004;5:307-309.