JOURNAL PRESENTATION

Dr. Nasrin Akhter

Resident (Phase B)

Department of Haematology,

BSMMU

Review article�� First Published: 13^TH August, 2019� on British Journal Of Haematology.�� Authors: Maximilian Stahl and Martin S. Tallman

Introduction

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• Differentiation syndrome (DS), also formerly known as retinoic acid syndrome can occur when patients with acute promyelocytic leukaemia (APL) are treated with the differentiating agents all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) .

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• APL DS is a common complication in the treatment of APL with a reported incidence ranging from 2% to 48% .

Introduction

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• This wide variation in the incidence of DS is explained by the application of different diagnostic criteria as well as the use of varied induction therapy regimens and prophylactic strategies in the treatment of APL.

OBJECTIVE

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• For the practicing clinician, it is essential to recognize early signs and symptoms of APL DS and quickly intervene.

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• As it can lead to severe, even life-threatening complications if left untreated .

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OBJECTIVE

This article will review :

Pathogenesis

↑Vascular permeability  → weight gain, effusions , pulmonary oedema , distributive shock

Endothelial damage  → organ hypoperfusion and ischemia, multi-organ failure

Diagnosis of APL DS

Signs and Symptoms

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• The early diagnosis of APL DS can be challenging as signs and symptoms are frequently nonspecific and can be caused by a multitude of other processes.

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• One of the subtler signs of APL DS is weight gain.

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• The frequency of clinical signs and symptoms of APL DS differ, based on whether patients present with moderate or severe DS.

Signs and Symptoms

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• Most common S/S are fever and myalgias, dyspnoea and hypotension, peripheral and pulmonary oedema as well as pleural and pericardial effusion .

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• Rare symptoms include, diffuse alveolar haemorrhage induced by endothelial damage and acute febrile neutrophilic dermatosis (Sweet syndrome).

Laboratory findings

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• On laboratory evaluation, leucocytosis and coagulopathy is frequently seen.

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• About half of the patients treated with ATRA + ATO, will develop leucocytosis .

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• Whereas, about a quarter of patients for ATRA + chemotherapy, will develop leucocytosis .

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Laboratory findings

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• The higher incidence of leucocytosis can be explained the lack of a strong cytoreductive component with ATRA + ATO.

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• Increased fluid retention can lead to an increase in myocardial stretch and release of the brain natriuretic peptide.

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• In more severe cases, organ dysfunction demonstrated by elevation of the creatinine, blood urea nitrogen levels and elevated liver function tests.

Imaging

• Chest imaging with a chest radiograph or computed tomography scan is recommended if there is a suspicion for APL DS .

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• The presence of findings on chest imaging depends on the severity of APL DS.

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• Up to 40% of patients with APL DS had no changes on a chest radiograph, however, this was true for only 11% with severe DS.

Imaging

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• Heart failure , fluid overload , pulmonary haemorrhage and pneumonia can present with similar findings on chest imaging and should be considered in the differential diagnosis of APL DS.

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• To clarify the diagnosis, further testing with an echocardiogram and a bronchoscopy with a bronchioalveolar lavage can be employed.

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Diagnosis

Diagnosis of APL DS

Features of DS present?

Fever ≥ 38°C

Weight gain > 5kg

Hypotension

Dyspnoea

Radiographic opacities

Plueral or pericardial effusion

Acute renal failure

Grading of DS severity

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Severe : ≥ 4 features

Moderate : 3 features

Indeterminate: 1-2 features

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Timing of APL DS

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• APL DS was seen to present in a bimodal time distribution with 47% and 25% of APL DS overserved during the first and third week of therapy.

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• While severe DS occurred earlier during the treatment course (median of 6 days), moderate DS appeared relatively later (median of 15 days)

Timing of APL DS

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• In patients treated with the AIDA regimen, APL DS occurred at a median of 12 days after starting ATRA therapy with a range of 0–46 days.

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• It is important to note that APL DS does not happen once a patient achieves a complete remission with induction therapy.

OUTCOME AND PROGNOSIS

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• Multiple prospective and retrospective studies have demonstrated that immediate treatment of APL DS with steroids has reduced APL DS-associated mortality to about 1% in comparison to 9% prior to routine administration of steroid.

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• The outcomes of severe APL DS also seem to be dependent upon its occurrence during treatment.

OUTCOME AND PROGNOSIS

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• Early severe APL DS is associated with a higher death rate during induction therapy and a higher frequency of mechanical ventilation.

• Additionally, higher frequency of pulmonary infiltrates and weight gain is seen in early severe DS.

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• Whereas in late severe APL DS, hypotension, fever, pericardial effusion and renal failure are more frequently seen.

MANAGEMENT

Prophylaxis of APL DS

Consider using prophylaxis if high risk for APL DS:

WBC ≥ 5×10⁹ /l OR Cr > 123 µmol/l

Prophylaxis strategies:

• Prednisone 0.5 mg/ kg per day on day 1 until end of induction therapy
• Dexamethasone 2.5 mg/m² every 12 h on days 1-15
• Prednisone 1 mg/kg per day on day 1-10

Treatment of presumed APL DS

Discontinuation of ATRA and ATO

• There is no routine recommendation of discontinue ATRA and ATO in APL DS.

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Treatment of presumed APL DS

Future directions

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• Specific biomarkers to confirm the diagnosis of APLD DS do not exist and the diagnosis is still frequently made without certainty before an empiric course of steroids is started.

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• It remains unclear whether APL DS prophylaxis should be given to all patients or only to those patients thought to be at high risk to develop APL DS.

Future directions

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• There is no uniformly agreed steroid administration schedule for APL DS prophylaxis and the role of cytoreductive agents in the prophylaxis of APL DS in patients with hyperleucocytosis is incompletely understood.

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• The lack of evidence-based data to answer these questions would be best overcome with well-controlled randomized studies.

Take-away points

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• There are no universally accepted diagnostic criteria for APL DS but the presence of any of the following factors justifies a presumptive diagnosis of APL DS and the empiric start of steroid therapy: dyspnoea, unexplained fever, weight gain >5 kg, unexplained hypotension, acute renal failure, a chest radiograph demonstrating pulmonary infiltrates or pleural or pericardial effusion.

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• Mimickers of APL DS including sepsis, pneumonia, heart failure, pulmonary embolism and DAH need to be ruled out.

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Take-away points

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• If a presumptive diagnosis of APL DS is made, dexamethasone 10 mg every 12 h should be started immediately. If there is no improvement within 24 h, the dosing frequency should be increased to every 6 h.

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• Steroid prophylaxis is used in some protocols for all patients while in other protocols it is reserved for high risk patients with a WBC ≥5×10⁹/l or a serum creatinine >123 mol/l.

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• This review article recommend the use of steroid prophylaxis for all APL patients treated with ATRA/ATO.

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