Acute promyelocytic leukemia (APL) From the worst to the best prognosis MUDr. Petr Pavlíček Internal Hematological Clinics FNKV and 3LF UK in Prague

APL is a subtype of acute myelogenous leukemia Acute promyelocytic leukemia is the first malignant disease highly curable with targeted therapy directed at a unique molecular abnormality The bleeding (due to coagulopathy) is the most notorious manifestation of the disease

APL Most patients are young, present with leukopenia, (leukocytosis in 20%) Abnormal cells from almost all patients have a balanced reciprocal translocation between chromosomes 15 and 17 Defining abnormality is a translocation of retinoic acid receptor alpha gene

t(15;17)

APL t(15,17) generates a fusion transcript joining the PML (promyelocyte) and RAR-α (retinoic acid receptor-α) genes

Blood cell developement. A blood stem cell goes through several steps to become a red cell, platelet or white blood cell

APL: Physiologic quantities of retinoic acid no longer sufficient to allow for cell differentiation

APL The fusion of PML and RARA results in expression of a fusion protein with altered functions It caused blocking differentiation of granulocytes

APL Physiologic level od retinoic acid with Pathological receptor (PML/RARa) Doesn´t work (No differenciation)

APL APL is unique among leukemias due to its sensitivity to all-trans retinoic acid (ATRA) the acid form of vitamin A ATRA allows differentiation of the immature leukemic promyelocytes into mature granulocytes Therapeutic level of ATRA overcomes block of differenciation

APL Unlike other chemotherapies, ATRA does not directly kill the malignant cells ATRA induces the terminal differentiation of the leukemic promyelocytes, these differentiated malignant cells undergo spontaneous apoptosis on their own

APL

The prognosis of APL was changed, from the worst among AML as it used to be, to currently the best. a cure rate of approximately 80% to 90% of patients can be expected (all AML 30%)

Case report patient (M, 25) visited his GP for headache, flu- like feeling, high temperatures over 38°C, Sorethroat, bleeding from tonsilae bleeding around incarnated foot-nails on thumbs no blood samples taken ATB treatment was started and … patient was sent home

Case report Treatment without effect, bleeding worsening, with new localization (gingiva), 4 day later another meeting with GP Sent to Hospital Blood samples taken next day WBC 18,2 G/l PLT 16 G/l Coagulopathy Hematologist consulted, patient sent to hematology department of faculty hospital Diagnose of high-risk APL established Succesful treatment started… full recovery

Take Home Message Acute promyelocytic leukemia is highly curable malignant disease The bleeding (due to coagulopathy) is the most notorious manifestation of the disease The disease is characterized by a chromosomal translocation involving Retinoic receptor alpha (RARα) gene - t(15,17) ATRA treatment induces the terminal differentiation of the leukemic promyelocytes

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