Guidelines Summary
Guidelines on acute promyelocytic leukemia (APL) have been published by the following organizations:
National Comprehensive Cancer Network recommendations
According to the NCCN, multidisciplinary testing (immonohistochemistry, cytochemistry and molecular genetic analysis) are needed to diagnose APL in accordance with the 2016 WHO classification system. An APL diagnosis requires APL morphology and either:
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t(15:17) by cytogenetics, or
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Promelocytic leukemia (PML)/retinoic acid receptor alpha (RARA) by molecular testing
Patients are further classified as low risk (WBC ≤10,000/μL) or high risk (WBC >10,000/μL) [16] .
Induction treatment
For patients who are at low risk, NCCN lists the following regimens [16] :
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All-trans-retinoic acid (ATRA), 45 mg/m2 in divided doses daily until clinical remission, plus arsenic trioxide (ATO), 0.15 mg/kg IV daily until bone marrow remission; alternatively, ATO may be given in a dose of 0.3 mg/kg IV on days 1–5 of week 1 and 0.25 mg/kg twice weekly during weeks 2–8
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In the ATRA-ATO regimen, an ATRA dose of 25 mg/m2 may be used in children and adolescents.
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If arsenic is unavailable or contraindicated, ATO can be replaced with idarubicin 12 mg/m2 on days 2, 4, 6, and 8 (category 1) or with a single dose of gemtuzumab ozogamicin 9 mg/m2 on day 5
The NCCN recommends proceeding with consolidation if the blood count has recovered by day 28 (platelet count > 100,000/μL, absolute neutrophil count [ANC] > 1,000/μL). Bone marrow (BM) aspirate and biopsy may be considered to document morphologic remissionl, but is optional. If a full course of induction treatment is not given or counts have not recovered by day 28–35, a BM aspirate and biopsy is recommended to document morphologic remissionl.
In patients who are at high risk and able to tolerate anthracyclines, NCCN recommends a choice of one of the following preferred regimens [16] :
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ATRA plus age-adjusted idarubicin (6–12 mg/m2 on days 2, 4, 6, 8) and ATO (0.15 mg/kg on days 9–36 as 2 h IV infusion)
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ATRA plus ATO 0.15 mg/kg/d IV; plus a single dose of gemtuzumab ozogamicin 9 mg/m2 given on day 1, 2, 3, or 4
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ATRA plus ATO 0.3 mg/kg IV on days 1–5 of week 1 and 0.25 mg/kg twice weekly on weeks 2–8 (category 1); plus a single dose of gemtuzumab ozogamicin 6 mg/m2 may be given on day 1, 2,3, or 4
Other recommended regimens are as follows:
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ATRA plus daunorubicin 50 mg/m2 × 4 days (IV days 3–6) plus cytarabine 200 mg/m2 × 7 days (IV days 3–9)
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ATRA plus daunorubicin (60 mg/m2 x 3 days) and cytarabine (200 mg/m2 × 7 days)
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ATRA plus idarubicin (12 mg/m2 on days 2, 4, 6, 8)
In patients who are at high risk and unable to tolerate anthracyclines, the NCCN recommends ATRA plus ATO. Induction is continued until count recovery and bone marrow remission are demonstrated. BM aspirate and biopsy are recommended at day 28 to document remission, with lumbar puncture considered before proceeding with consolidation. [16]
Consolidation Therapy
For consolidation therapy, the NCCN recommends basing the choice of regimen on the agents used for induction therapy. For example, patients who received ATRA/ATO would continue to receive that regimen, while those treated with ATRA plus chemotherapy would for the most part continue to receive those agents. In some cases, mitoxantrone may be added. [16]
NCCN guidelines note that the role of maintenance therapy remains uncertain, especially for patients with low-risk APL who achieve molecular remission at the end of consolidation treatment. Most of the studies demonstrating benefit from maintenance therapy were conducted before the introduction of ATRA, ATO, or cytarabine for consolidation. [16]
European LeukemiaNet recommendations
ELN recommendations for management of APL are as follows [48] :
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Immediately admit patients with suspicion of APL to the hospital, initiate ATRA, and manage coagulopathy. Confirmation of APL by genetic diagnosis should follow.
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Monitor coagulation parameters at least daily until all signs of coagulopathy have disappeared.
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Initiate transfusions immediately and continue them to maintain appropriate fibrinogen concentration, platelet count, and international normalized ratio.
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Start cytoreductive therapy with ATRA upon suspicion of APL. High-risk patients should also receive chemotherapy, and low-risk patients may receive antileukemic agents upon genetic diagnosis of APL. In view of the demonstrated efficacy of ATRA/ATO, the ELN recommends its use for low-risk patients as well as for patients not receiving chemotherapy.
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After consolidation therapy, perform a bone marrow molecular assessment to confirm complete response (CR) with negative minimal residual disease (MRD). The ELN does not recommend routine monitoring after induction therapy or in low-risk patients with CR and negative MRD after consolidation.
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In high-risk patients, monitor MRD every 3 months for up to 3 years after consolidation.
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In low-risk patients, the ELN does not recommend maintenance therapy after consolidation.
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Continue maintenance therapy in high-risk patients receiving ATRA and chemotherapy who showed clinical benefit.
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Elderly patients with good clinical conditions should receive the same treatment as younger patients, with a small dose reduction similar to the treatment of low-risk patients with APL.
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Patients with evidence of molecular or hematologic relapse after consolidation should be crossed over according to the previously used treatment: patients who previously received ATRA plus ATO should receive ATRA plus chemotherapy and vice versa. Perform autologous hematopoietic stem cell transplantation in patients who have achieved second molecular remission, have negative MRD, or are have negative results on polymerase chain reaction (PCR) testing.
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Tthe patient’s individual genetic variants of APL should inform treatment: Patients with ATRA-sensitive variants should be treated with ATRA and anthracycline chemotherapy, while those with ATRA-resistant variants might not benefit from ATRA treatment.
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Bone marrow aspirate hybridized with the RARA dual color break-apart probe set (Abbott-Vysis). The cell to the left shows a normal cell with 2 fusion signals, as the 5'RARA probe (orange) and the 3'RARA probe (green) are not separated. The cell on the right shows split signals for one RARA gene, indicating a chromosomal rearrangement disrupting the RARA gene. Image courtesy of Dr. Tina Edmonston from the Department of Pathology at Thomas Jefferson University Hospital.
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Bone marrow aspirate hybridized with PML/RARA dual color translocation probe set (Abbott-Vysis). The cell to the right shows a normal cell with 2 separate PML (orange) and RARA (green) signals each. The cell to the left shows an abnormal cell characterized by a single fusion signal juxtaposing the PML and RARA signals, suggestive of a translocation of the 2 genes. Images courtesy of Dr. Tina Edmonston from the Department of Pathology at Thomas Jefferson University Hospital.
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Hypogranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.
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Regularly hypergranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.
