Promyelocytic leukemia
| Classification according to ICD-10 | |
|---|---|
| C92.4 | Acute promyelocytic leukemia |
| ICD-10 online (WHO version 2019) | |
The promyelocytic leukemia (often abbreviated as M3, APL or APML) and the variant form (m3v) belong to the group of acute myeloid leukemia (AML), it is an extremely rare form.
The differential blood count shows promyelocytes with Auer rods and the typical promyelocytic granulation (primary granules ). A typical feature is also the positive peroxidase (cytochemical staining). The first suspected diagnosis is usually made on the basis of the microscopic image. Further clarification is carried out by means of a cytogenetic examination and detection of the characteristic translocation t (15; 17).
Causes and origins
The most common cause is a t (15; 17) translocation, which results in a fusion of the two genes coding for the transcription factors promyelocytic leukemia protein (PML) and retinoic acid receptor-α (RARα).
RAR binding in the absence of the ligand all-trans-retinoic acid ( tretinoin , engl . All-trans retionic acid, short form of all- trans RA or ATRA) to the DNA and interacts with a complex for transcription repression which histone deacetylases (HDAC) recruited. Deacetylation of the histones results in the formation of heterochromatin and thus a suppression of transcription .
The oncogenic fusion protein (PML / RAR alpha ) maintains this interaction even in the presence of the ligand, which results in a constitutive suppression of the RARalpha -regulated genes. This leads to a transcriptionally suppressed differentiation blockade and thus to impaired cell maturation of the promyelocytes.
diagnosis
Diagnosis should be based on genetic detection of the PML-RARA fusion protein, RT-PCR assay , detection of t (15; 17) translocation using conventional karyotyping or fluorescence in situ hybridization , or detection of the for the promyelocyte leukemia typical microspeckling of promyelocytes in the indirect immunofluorescence assay .
therapy
In addition to chemotherapy based on anthracyclines , two agents are used as a supplement or alternative that are specific for this form of leukemia and that, together with chemotherapy, show very good therapeutic results. Both agents work synergistically in the degradation of the oncoprotein that causes leukemia:
- Tretinoin (all-trans retinoic acid, ATRA) binds to the RAR alpha part of the oncoprotein and leads to its degradation. This leads to the lifting of the HDAC-dependent differentiation blockade. ATRA was introduced in the 1980s and revolutionized the therapy of this leukemia subtype, which was previously considered the form with the worst prognosis. It was the first therapy with a specific effect on the causative oncoprotein.
- Arsenic trioxide binds to the RBCC domain ( RING finger, B box and coiled coil domain ) of the PML part of the fusion oncoprotein PML / RAR alpha , which leads to its degradation. As a result, the differentiation stop by the oncoprotein is lifted, the tumor cells differentiate further and apoptosis of the partially differentiated tumor cell is induced. It was used as a therapy for promyelocytic leukemia in China as early as the 1970s.
The standard of therapy in 2013 is a combination of anthracycline chemotherapy and all-trans retinoic acid, which leads to a remission in 95% and a permanent cure in 80%.
In a multicentre randomized controlled phase III study with 156 patients with promyelocytic leukemia and a low to intermediate risk, the combination of ATRA and arsenic trioxide was compared to the standard therapy of ATRA and anthracycline. Here, showed up at a median follow-up of 34 months, a complete remission ( complete remission ) in the Arsentrioxidgruppe at 100% to 97% in the anthracycline group, as well as a complication-free two-year survival rate of 97% and 86%, which ATRA and arsenic trioxide were no less effective than the standard of ATRA and anthracycline. With arsenic trioxide, fewer infections and fewer haematological complications were observed, but more hepatotoxic problems.
Individual evidence
- ↑ Francesco Lo-Coco, Giuseppe Avvisati, Marco Vignetti and others: Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia. In: New England Journal of Medicine . 2013, Volume 369, Issue 2 of July 11, 2013, pp. 111-121; doi: 10.1056 / NEJMoa1300874