Acute promyelocytic leukemia classification

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [3]

Overview

There are several broad classification schemes for acute promyelocytic leukemia. The most well-accepted classification scheme is risk-based classification, which categories patients into low-risk, intermediate-risk, or high-risk based on the white blood cell count and platelet count. Another classification scheme is based on the origin of the leukemia, which categorized patients as having de novo or therapy-related disease. A final classification scheme is cytogenetic-based, in which case specific chromosomal abnormalities are used to stratify patients.

Classification

Based on Risk

• Low-risk disease:
  • Low-risk disease is defined as the presence of less than 10000 white blood cells per microliter and greater than 40000 platelets per microliter in the peripheral blood.
  • Treatment of low-risk disease involves non-chemotherapy-based regimens, such as the combination of all trance retinoic acid and arsenic trioxide.
• Intermediate-risk disease:
  • Intermediate-risk disease is defined as the presence of less than 10000 white blood cells per microliter and less than 40000 platelets per microliter in peripheral blood.
• High-risk disease:
  • High-risk disease is defined as the presence of greater than 10000 white blood cells per microliter in peripheral blood, regardless of the platelet count.
  • Platelet count is typically less than 40000 cells per microliter, though platelet count is not a formal criterion in the classification of acute promyelocytic leukemia.

Based on etiology

• De novo disease:
  • De novo acute promyelocytic leukemia is the most common subtype.
  • This refers to development of the disease in the absence of prior cytotoxic therapy or prior precursor conditions.
  • De novo acute promyelocytic leukemia is due to a sporadic events in cells, without prior DNA damaging insults. This is in contrast to therapy-related disease.

• Therapy-related disease:
  • Therapy-related disease refers to the development of acute promyelocytic leukemia in patients who were previously treated with DNA-damaging or genotoxic agents for other conditions, such as other cancers.
  • The most common DNA-damaging agents that cause therapy-associated acute promyelocytic leukemia are topoisomerase inhibitors and alkylating agents.
  • Therapy-related acute promyelocytic leukemia is typically seen in patients with a history of breast cancer who received cyclophosphamide or patients with a history of a germ cell tumor who have received etoposide.
  • The prognosis of therapy-related disease is worse than that of de novo disease, with a 5-year survival of less than 10 years. The 4-year overall survival for therapy-related disease is 24.5%, compared to 39.5% for de novo disease.

Chemotherapeutic agents
Topoisomerase II inhibitors:	This class of chemotherapeutics causes early-onset leukemia, with a typical latency of 2-3 years from the receipt of the topoisomerase inhibitor. Cytogenetics from the leukemia diagnosis typically shows the MLL rearrangement (chromosome 11q23). There is usually no preceding myelodysplastic phase; the onset of leukemia is relatively sudden.
Alkylating agents:	This class of chemotherapeutics causes late-onset leukemia, with a typical latency of greater than 7 years from the receipt of the alkylating agent. Cytogenetics from the leukemia diagnosis typically shows monosomy 5 or monosomy 7. Mutational analyses can show a TP53 mutation. There is usually a preceding myelodysplastic phase.
Other chemotherapeutic agents:	Although other chemotherapy medications are not classically associated with therapy-related apromyelocytleukemiamiaiamia, there have been cases of such associations. In a patient with gastric cancer treated with oxaliplatin and capecitabine, acute promyleukemia leukemia developed after a latency period of 4 years. The leukemic cells had chromosomal abnormalities, suggesting that the secondary neoplasm was chemotherapy-induced rather than de novo.

Based on cytogenetics

• The karyotype of most cases of acute promyelocytic leukemia involves the t(15;17) translocation between the PML and RARA genes. However, complex karyotypes may co-exist in some cases of acute promyelocytic leukemia.

Cytogenetics
Complex karyotype	Complex karyotype is defined as the presence of two or more chromosomal abnormities. Complex karyotype acute promyelocytic leukemia is associated with worse prognosis and lower rates of complete remission, similar to complex karyotype acute myeloid leukemia. Patients with complex karyotype are more likely to have a TP53 mutation and are more likely to be resistant to chemotherapy.
Trisomy 8	Trisomy 8 is characterized by three copies of chromosome 8 in cells. This chromosomal abnormality is commonly found in patients with myelodysplastic syndrome, which is a precursor condition for acute myeloid leukemia. Aside from t(15;17), trisomy 8 is the most frequent chromosomal abnormality in acute promyelocytic leukemia.
Tetraploidy	Tetraploidy is defined as the presence of four sets of chromosomes in a cell. Tetraploidy is generally rare in acute promyelocytic leukemia and accounts for approximately 0.75% of cases. The karyotype of most cases of acute promyelocytic leukemia involves the t(15;17) translocation between the PML and RARA genes. However, complex karyotypes may co-exist in some cases of acute promyelocytic leukemia. Tetraploidy in acute promyelocytic leukemia is more commonly associated with CD2 expression in the malignant cells. Tetraploid acute promyelocytic leukemia is mostly sensitive to all-trans retinoic acid.
t(8;21)	The t(8;21) translocation sometimes co-exists with the t(15;17) translocation. The t(8;21) translocation is more commonly found in acute myeloid leukemia and involves the juxtaposition of the ETO (RUNX1T1) gene on chromosome 8 with AML1 (RUNX1) gene on chromosome 21. A total of six cases of coexisting t(8;21) and t(15;17) have thus far been described.