Page 1431 - Williams Hematology ( PDFDrive )

1406 Part X: Malignant Myeloid Diseases Chapter 88: Acute Myelogenous Leukemia 1407

Chemotherapy Induction of remission with ATRA alone is fol- Maintenance Therapy After consolidation phases of therapy are
lowed by relapse in weeks to months unless intensive chemotherapy is complete, patients should be in a molecular remission, that is, PCR-
used concomitantly. At relapse, cells show high levels of a cytosolic negative for PML-RAR-α. ATRA maintenance with chemotherapy is
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retinoic-acid-binding protein not detected prior to ATRA therapy. recommended based on the APL 93 trial, which showed that relapse-
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The mechanism of retinoid resistance in leukemic cells may involve free survival was superior with ATRA versus no ATRA, and that the
cytochrome P450 and P-gp because of induction of various enzymes best results were achieved when ATRA was combined with 6-mercap-
that may alter ATRA metabolism. ATRA, whether administered as topurine and methotrexate. The 10-year cumulative relapse rates were
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part of induction therapy or as maintenance therapy, confers a disease- 43 percent with no maintenance, 33 percent with ATRA alone, 23 per-
free survival advantage. More than 70 percent of patients receiving cent with chemotherapy alone, and 13 percent with ATRA and chemo-
ATRA at any point were in continuous remission at 2.5 years versus less therapy. Maintenance is usually recommended for 2 years, and studies
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than 20 percent of patients who never received ATRA. The acquired to examine whether maintenance is beneficial in low-risk disease are
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in vivo resistance that occurs rapidly to ATRA as a single agent requires ongoing. During maintenance, PCR monitoring on blood samples is
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consolidation of ATRA-induced complete remission with intensive recommended. If the PCR is positive in blood, a marrow examination
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chemotherapy using an anthracycline antibiotic. Customary treatment should be done.
today involves simultaneous administration of ATRA and an anthracy- Treatment for Relapsed Acute Promyelocytic Leukemia Con-
cline and/or arsenic trioxide. Some therapists have returned to combin- ventional chemotherapy can be effective after relapse. Arsenic trioxide
ing an anthracycline antibiotic with cytarabine in an effort to decrease has been used in those who do not achieve molecular remission at com-
CNS relapse, especially in patients younger than 60 years of age with pletion of consolidation or who subsequently demonstrate molecular
white counts greater than 10 × 10 /L at presentation. Maintenance relapse and can generate high molecular remission rates in more than 80
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therapy with ATRA alone or in combination with mercaptopurine or percent of patients alone or when combined with chemotherapy. It is
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methotrexate has been recommended. This additional therapy has not still uncertain whether ATRA has benefit in patients previously exposed
been examined in a randomized trial of ATRA dosing and scheduling, to ATRA. Patients younger than age 70 years should be considered for
but ATRA usually is given in an interrupted fashion. Intensified main- allogeneic or autologous HSC transplantation after they have achieved a
tenance therapy may have a negative impact on those patients who have second remission or for allogeneic transplantation if a second remission
become negative for the PML-RAR-α fusion transcript after induc- cannot be induced. Other treatments for patients in relapse include
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tion plus consolidation therapy. Some therapists have proposed that the combination of ATRA, arsenic trioxide, and gemtuzumab ozogami-
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elderly patients can be treated with ATRA and arsenic trioxide without cin. This combination has resulted in durable remissions. Transplan-
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chemotherapy and with addition of gemtuzumab ozogamicin in the tation generally is not recommended for patients with APL in first
event of an elevated white count at the time of diagnosis. 958 remission given the prolonged remissions after standard treatments.
Arsenic Trioxide Arsenic trioxide can trigger apoptosis of APL Allogeneic stem cell transplant is best used in advanced APL, especially
cells at high concentrations and maturation at low concentrations. in patients with persistent disease by PCR. The outcome of autologous
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The presence of PML-RAR-α is important for the response. Apoptosis stem cell transplantation in second complete remission is excellent if the
may occur through induction of activation of caspase-1 and caspase-3 stem cells used are negative for PML-RAR-α. High-dose cytarabine
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after changes in the mitochondrial membrane potential with increase can be used for stem cell mobilization which will also treat CNS relapse,
in H O . 2 959,960 It also may function through NF-κB inhibition. Death- and when a second molecular remission is followed by an autograft, the
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2
associated protein 5 also contributes to arsenic trioxide–induced 5-year disease-free survival is approximately 75 percent. This result is
apoptosis in APL. Arsenic trioxide given at 0.06 to 0.12 mg/kg body superior to survival after allografting, but a direct comparison of autol-
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weight per day until leukemic cells were eliminated from the marrow ogous transplantation, allogeneic transplantation, and arsenic trioxide
induced remission within 12 to 89 days in 11 of 12 patients. Suppres- or ATRA with standard chemotherapy has not been made in patients
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sion of hematopoiesis did not occur. Rash, light-headedness, fatigue, with APL in a second remission after relapse. For patients in a second
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and musculoskeletal pain were the main side effects. Arsenic trioxide remission who are not candidates for allogeneic stem cell transplant, up
can be combined with idarubicin in relapsed patients; it also has been to six cycles of arsenic can be used.
used with ATRA. 921,964,965 A retinoic acid–like syndrome (see “All-Trans- Many cases of extramedullary relapse in APL have been reported.
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Retinoic Acid: Dose and Mechanism of Action” above) has been Many of the relapses occur in patients who received ATRA and who
described in patients with APL treated with arsenic trioxide. Torsade initially were diagnosed with hyperleukocytosis, and many of the
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de pointes, an uncommon variant of ventricular tachycardia in which patients are in marrow remission. Relapses occurring more than 5 years
the underlying etiology and management are different from those of the after diagnosis have been reported, some at extramedullary sites such
usual variety of ventricular tachycardia, has been described with arsenic as in the mastoid bone. Early detection of relapse is important as
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trioxide use, and monitoring of electrocardiographic QTc intervals those with molecular relapse before hematologic relapse has occurred
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and electrolyte levels during therapy is recommended. 968 fare best. Patients should be monitored with PCR every 3 months for
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Consolidation Therapy Consolidation therapy is required in 2 years after remission induction, especially those with intermediate- or
APL to achieve a durable molecular remission. Consolidation typically high-risk disease. 928
consists of anthracycline plus ATRA, but in high-risk patients, the addi- MDS can occur in patients in remission with APL, usually
tion of cytarabine or use of arsenic trioxide can be used to diminish the 24 months or more after diagnosis. The complication results from a sec-
rate of relapse. Almost every induction regimen described in APL has ond (drug-induced) clonal disease in long-term responders. 980–992 Cases
a distinct consolidation regimen attached to it, dependent on disease of therapy-related APL have been described. Patients with APL who
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stratification. To achieve uniformly good responses, it is recommended are FLT3-ITD–positive generally have worse overall outcomes than do
that one follow a given protocol’s induction, consolidation, and mainte- those persons who present with elevated white cell counts and older
nance regimen. Table 88–8 provides examples of paired induction and age. There is also evidence that mutations in the ATRA-targeted ligand
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consolidation regimens. Excellent results can be achieved with all of binding domain of PML-RAR-α and additional chromosome abnormal-
these regimens, if treatment plans are executed faithfully. ities may be associated with reduced postrelapse survival in those on

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