Differentiation Syndrome; Post-ATRA/ATO Induction Therapy in Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a disease described as de�nite morphological and cytogenetical abnormalities and leads to coagulopathy leaving the patient in a life-threatening condition. A speci�c chromosomal translocation of 15 and 17 chromosomes leads to retinoic acid receptor-α ( RAR α ) and promyelocytic leukemia (PML) genes fusion that produces an abnormal gene mutation forming an oncogenic protein which is (PML-RAR α ). Those APL patients, who have been treated with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) usually ends up in a complicated condition called differentiation syndrome which is rarely severe. This case report explains the 37-years old male diagnosed with acute promyelocytic leukemia and later developed a differentiation syndrome after initiation of all-trans retinoic acid and arsenic trioxide induction therapy.

peripheral smear to assess the cell morphological changes.The abnormal cells are bi-lobular, creased nuclei and many violet color granules (Auer rods) in the cytoplasm [ 4 ] .D i a g n o s i s o f A P L i n c l u d e s c y to c h e m i s t r y, immunohistochemistry, and analysis of molecular genetics according to the WHO classi cation system [4].Patients managed with ATRA or ATO have complicated condition called differentiation syndrome which is rarely severe.The characteristic symptoms of differentiation syndrome include dyspnea, fever, hypotension, weight gain, acute kidney injury, and changes in the chest radiograph indicating in ltrates [5].The treatment with ATRA or ATO has increased the prognosis by improving the remission Acute Promyelocytic Leukemia

I N T R O D U C T I O N
Acute promyelocytic leukemia (APL) is a disease described as de nite morphological and cytogenetical abnormalities and leads to coagulopathy leaving the patient in a life-threatening condition.A speci c chromosomal translocation of 15 and 17 chromosomes leads to retinoic acid receptor-α (RARα) and promyelocytic leukemia (PML) genes fusion that produces an abnormal gene mutation forming an oncogenic protein which is (PML-RARα).Those APL patients, who have been treated with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) usually ends up in a complicated condition called differentiation syndrome which is rarely severe.This case report explains the 37-years old male diagnosed with acute promyelocytic leukemia and later developed a differentiation syndrome after initiation of all-trans retinoic acid and arsenic trioxide induction therapy.

CASE REPORT
A 37-year-old male with no-known co-morbid readmitted to the hospital in the emergency department with complaints of fever, and blood in the urine.Bone marrow analysis was done on the previous admission to rule out 9 9 bicytopenia (WBC-0.7*10/L and Platelets-7*10 /L) and results were consistent with APL.Flow cytometry and PML RARA were obtained.The patient and the family were counseled regarding the situation, risks, and various options for treatment along with the plan of care.The patient was then initiated with ATRA and ATO.During treatment the patient started experienced worsening shortness of breath, chest x-ray showed minimal basal atelectasis (Figure 1 and 2).ATRA and ATO administration was stopped and supplemental oxygen therapy, steroids, antibiotics, and diuretics started.The oxygen requirement increased and patient was electively intubated and managed along the lines of differentiation Syndrome.
after the initiation of induction therapy with ATRA or ATO, or both in patients with APL.The incidence of cases with DS after the initiation of treatment, according to the standardized doses is approximately 2 to 27% after the administration of ATRA and approximately 7 to 31% after ATO [7].According to the systematic review, it is found that the incidence of DS individually with ATRA is 17.4% whereas those who treated with ATRA and ATO are 23.3% [8].Fever and common respiratory signs and symptoms are the speci c features seen in patients with differentiation syndrome [6].The onset of differentiation syndrome with the initiation of therapy is within days to weeks, but it varies from patient to patient [9].The incidence of symptoms with differentiation syndrome include dyspnea (77%), pleural effusion (43%), pericardial effusion (17%), fever (64%), weight gain (53%), generalized edema (67%), acute renal failure (28%), and hypotension (26%) [10].The pathophysiology of DS is not known but it has been discovered that the administration of ATRA induces a pathophysiologic response and leads to initiate systemic i n a m m a t o r y r e s p o n s e sy n d r o m e ( S I R S ) .T h e in ammatory response activates the release of tumor necrosis factor-α and cytokines like interleukin-1, which is mostly involved in the damage of endothelial cells [9].As a result of in ammation, blast cell in ltration occurs in the lungs.It is a similar mechanism in which the normal granulocytes migrate to the site of in ammation and the circulating leukocytes were taken by the endothelium cells.
The transmigration through the endothelial cell requires protease secretion which ultimately disrupts the barrier.Extravasation of uid that occurs in the lung leads to pleural effusion [11].The management of DS include administration of corticosteroids at the rst suspicion and diagnostic testing is in progress.For immediate response, corticosteroids may be used twice a day to decrease the severity of symptoms.Moreover, hydroxyurea may be initiated in patients with associated leukocytosis.In edematous or patients with pleural effusion, the most common drug of choice is furosemide.Therefore, patients experiencing severe pulmonary and renal symptoms require close monitoring and hospitalization [12].ATRA has been widely used for the management of APL for decades and along with induction therapy with ATRA, it is recommended to simultaneously treat patients with a higher dose of dexamethasone in those who have signi cant symptoms of DS [13].Furthermore, it is found that combination therapy of ATRA and ATO have a high effect on patients with APL regardless of any risk.A randomized control trial study showed that treatment of APL with ATRA or ATO or both in all risk groups showed the same results with increased cure, less relapse, and no difference in survival rate [14].Therapy can be temporarily

D I S C U S S I O N
Differentiation syndrome is a serious di culty that arises

Figure 1 :Figure 2 :
Figure 1: At the initiation of symptoms