Differentiation (Retinoic Acid) Syndrome

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Official reprint from UpToDate

www.uptodate.com 2013 UpToDate

AuthorsSteven E Weinberger, MDRichard A Larson, MD

Section EditorKevin R Flaherty, MD, MS

Deputy EditorsHelen Hollingsworth, MDRebecca F Connor, MD

Differentiation (retinoic acid) syndrome

Disclosures

All topics are updated as new evidence becomes available and ourpeer review process is complete.Literature review current through: Apr 2013. | This topic last updated: jul 18, 2012.

INTRODUCTION The differentiation syndrome (previously called "retinoic acid syndrome") is a potentially fatal

complication of induction chemotherapy in patients with acute promyelocytic leukemia (APL). It is characterized by

fever, peripheral edema, pulmonary opacities, hypoxemia, respiratory distress, hypotension, renal and hepatic

dysfunction, rash, and serositis resulting in pleural and pericardial effusions. It is a cytokine release syndrome,

sometimes called "cytokine storm," and all of the pathophysiologic consequences result from the release of

inflammatory cytokines from malignant promyelocytes, probably independent of their differentiation to segmented

neutrophils and hyperleukocytosis.

The differentiation syndrome occurs in approximately 25 percent of patients with APL during induction therapy that

includes all-trans retinoic acid (ATRA, also known as tretinoin) orarsenic trioxide (ATO), but it is also seen in

untreated patients or after other cytotoxic therapies. Early recognition and aggressive management are essential.

The pathogenesis, clinical presentation, diagnosis, and treatment of differentiation syndrome will be discussed

here. The pathogenesis, diagnosis, and treatment of APL are presented separately. (See "Clinical manifestations,

pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Initial treatment of acute

promyelocytic leukemia in adults" and "Treatment of relapsed or refractory acute promyelocytic leukemia inadults".)

EPIDEMIOLOGY Differentiation syndrome occurs in approximately 25 percent of patients treated with all-trans

retinoic acid (ATRA) orarsenic trioxide (ATO) as induction therapy for acute promyelocytic leukemia (APL). In

addition, it also occurs in patients with relapsed or refractory APL who are treated with these agents. The risk of the

syndrome is not a function of the dose of eitherof these agents, nor is it proportional to the WBC count.

Differentiation syndrome is not observed when ATRA and/or ATO are used as consolidation or maintenance

therapy for APL, nor does it complicate ATRA or ATO treatment of non-APL malignancies [1]. This syndrome

depends on the presence of malignant promyelocytes. For example, APL is the most common acute leukemia to

present with non-infectious fever, and this is thought to be due to the release of cytokines even before treatment is

initiated.

While the reported incidence rates of differentiation syndrome have ranged from 2 to 27 percent in patients treated

with standard doses of ATRA and 30 percent in patients treated with ATO, this variation is at least partially due to

the use of different diagnostic criteria among studies [1-4]. The incidence may be lower when ATRA is administered

concurrently with induction chemotherapy or prophylactic glucocorticoids [1,5]. (See 'Prevention' below and "Initial

treatment of acute promyelocytic leukemia in adults", section on 'ATRA plus chemotherapy'.)

One of the largest studies analyzed 739 patients with newly diagnosed APL treated with ATRA plus idarubicin for

induction as part of two prospective trials [ 6]. Differentiation syndrome was diagnosed in 25 percent 13 percent
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were severe and 12 percent were moderate.

As yet, no factors reliably predict which patients are more or less likely to develop dif ferentiation syndrome after

treatment with ATRA or ATO. An increased incidence has been reported in patients with an elevated white blood

cell (WBC) count at diagnosis, a rapidly increasing WBC count, expression of CD13 on APL blasts, or an elevated

body mass index (BMI), although only a high BMI has been confirmed as a risk factor in subsequent studies [ 7-14].

It is important to recognize that the syndrome can occur in the absence of an elevated WBC count.

PATHOGENESIS The etiology of the differentiation syndrome is incompletely understood, but is thought to be

due to release of inflammatory vasoactive cytokines, causing capillary leak, fever, edema, rash, and hypotension

[15]. It has also been linked to the maturation of promyelocytes induced by all-trans retinoic acid (ATRA) orarsenic

trioxide (ATO), followed by tissue infiltration by the maturing cells [16], but this may be a secondary phenomenon.

Acute promyelocy tic leukemia (APL) is characterized by the presence of an abnormal PML-RARa f usion gene that

encodes a protein, which functions as an aberrant retinoid receptor. This PML/RARa protein heterodimerizes with

the retinoid X receptor (RXR) the resulting PML/RARa-RXR complex binds to retinoic acid responsive elements in

target genes. This interaction blocks myeloid differentiation at the promyelocytic stage. ATRA and ATO induce

differentiation of the malignant myeloid clone by dissociating the PML/RARa-RXR complex from the target genes.

This leads to a sudden increase in differentiated myelocytes and neutrophils that is believed to contribute to the

pathogenesis of differentiation syndrome. (See "Molecular biology of acute promyelocytic leukemia", section on

'Retinoic acid and the retinoic acid receptor'.)

Patients treated with ATRA or ATO who develop differentiation syndrome demonstrate interstitial edema and

infiltration of the lung, lymph nodes, spleen, liver, and pericardium with maturing myeloid cells [ 2]. Three general

theories have been proposed to explain the infiltration of myeloid cells into the lung and other tissues:

ATRA and ATO may induce release of cytokines from differentiating myeloid cells that cause a capillary

leak syndrome. In vitro studies have demonstrated a strong upregulation of chemokine production by APL

cells after treatment with ATRA and/or ATO [ 17]. In addition, the administration of vasoactive cytokines (eg,

interleukin-2 for renal cell carcinoma) produces a number of features of the differentiation syndrome,

including fever, generalized weight gain, and episodic hypotension [ 18]. (See "Immunotherapy of renal cell

carcinoma", section on 'Interleukin-2'.)

ATRA and ATO may enhance the migration of maturing leukocytes, with subsequent organ infiltration

resulting in respiratory and renal dysfunction [19].

ATRA and ATO may induce upregulation of the expression of integrins (cellular adhesion molecules) in

leukocytes, resulting in their increased adherence to capillary endothelium and consequent capillaritis [20-

23].

These proposed mechanisms are not mutually exclusive, and it is likely that some of these and other, not yet

identified, mechanisms contribute to the pathogenesis of differentiation syndrome.

CLINICAL PRESENTATION The onset of clinical manifestations of the differentiation syndrome follows a

bimodal pattern with 46 percent of patients developing clinical manifestations within one week and 38 percent

developing symptoms between the third and fourth weeks of starting all-trans retinoic acid (ATRA) orarsenic

trioxide (ATO) [6]. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic

leukemia in adults".)

Symptoms and signs The typical symptoms and signs of the differentiation syndrome include fever,

hypotension, dyspnea, weight gain of more than 5 kg, and musculoskeletal pain [ 2,4,6,7,24,25]. Patients with more

severe disease tend to manifest a greater number of these symptoms and signs [6]. Diffuse erythematous rash
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may also be present. The following list shows the range of frequencies of the more common manifestations:

Dyspnea (59 to 95 percent)

Edema (53 to 81 percent)

Unexplained fever (53 to 74 percent)

Hypotension (12 to 39 percent)

Pulmonary hemorrhage is a well-described complication however, its incidence is unclear [ 3,26], and it may reflect

concurrent severe thrombocytopenia. Sweet syndrome (acute febrile neutrophilic dermatosis) has also been

reported as a complication of differentiation syndrome [27,28]. (See "Sweet syndrome (acute febrile neutrophilic

dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)

Laboratory A variety of hematologic abnormalities are noted in patients with the differentiation syndrome,

including anemia, thrombocytopenia, and coagulopathy requiring plasma transfusion [6]. Some of these

abnormalities may be due to the underlying acute promyelocytic leukemia (APL) and concomitant chemotherapy.

Patients with APL are monitored daily with complete blood counts. Although an increasing WBC count may be a

risk factor for differentiation syndrome, no exact WBC count is predictive or diagnostic. In one series, the median

count at the onset of the differentiation syndrome was 31,000/microL (31 x 10(9)/L) [ 7].

Imaging

Chest radiographs A chest radiograph is typically obtained to evaluate dyspnea, cough, or fever. The main

findings on chest radiography are an increased cardiothoracic ratio (87 percent), septal lines and peribronchial

cuffing (87 percent), ground glass opacity (60 percent), parenchymal consolidation (47 percent), nodular opacities

(47 percent), air bronchogram (33 percent), and pleural effusion (73 percent) [ 3,6]. Radiographic opacities often

mimic the patterns seen with pulmonary edema or an infectious pneumonia in a febrile neutropenic patient. Ground

glass opacity tends to be diffuse, involving most or all lung zones [ 3]. However, approximately 40 percent of

patients with differentiation syndrome have a clear chest radiograph at presentation, although only 11 percent of

patients with severe disease have a clear chest radiograph, so treatment of the differentiation syndrome should not

be delayed by waiting for the radiograph to become abnormal [ 6].

Computed tomography The chest computed tomography (CT) findings associated with the differentiationsyndrome are nonspecific and may include diffuse ground glass opacities, subpleural nodular opacities, septal

thickening, pleural and pericardial effusions, and patchy consolidation (image 1) [6]. Among patients with

documented pulmonary hemorrhage, poorly defined centrilobular nodules, areas of consolidation, and diffuse ground

glass opacities may be seen [22].

CT pulmonary angiography may also be used to exclude pulmonary thromboembolism. (See 'Differential diagnosis'

below and "Diagnosis of acute pulmonary embolism".)

Bronchoscopy and bronchoalveolar lavage Bronchoscopy and bronchoalveolar lavage (BAL) are rarely

necessary, but can be used in the setting of suspected differentiation syndrome to evaluate for pulmonary

hemorrhage and infection, rather than to make a positive diagnosis of differentiation syndrome.

Approximately 77 percent of patients with APL have a platelet count of 40,000/mic roL (40 x (10)9/L) or less and/or

a coagulopathy at presentation [6]. While thrombocytopenia and/or an uncorrected coagulopathy are relative

contraindications for endobronchial or transbronchial biopsy, bronchoalveolar lavage can usually be safely

performed. The contraindications to bronchoscopy are discussed separately. (See "Flexible bronchoscopy:

Indications and contraindications", section on 'Contraindications'.)

The BAL technique for identifying pulmonary hemorrhage includes three sequential lavages in a single site. The

effluent typically shows increasingly hemorrhagic fluid with each successive sample (picture 1). This is confirmed
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by cytologic studies showing hemosiderin-laden macrophages. (See "The diffuse alveolar hemorrhage syndromes",

section on 'Bronchoalveolar lavage'.)

Lavage samples are also processed for bacterial, fungal, and mycobacterial smear, special stains, and culture.

Samples can also be sent for viral culture.

Lung biopsy Lung biopsy via video-assisted thoracoscopy or an open procedure is rarely performed, due to the

increased risk from aberrant coagulation and the prompt improvement that most patients have with the institution of

systemic glucocorticoid therapy.

In patients with the differentiation syndrome, the main pathologic finding is interstitial infiltration with maturing

myeloid cells [2]. Patients with fatal differentiation syndrome may also have evidence of septal edema, diffuse

alveolar damage, intraalveolar hemorrhage, and capillaritis [3,22].

Post-mortem studies have revealed extensive infiltrates of myeloid cells in other organ systems, including lymph

nodes, spleen, liver, and pericardium [2].

DIAGNOSIS Diagnosis of the differentiation syndrome requires a high index of suspicion, but the diagnosis is

typically made clinically based on the appropriate setting for patients with acute promyelocytic leukemia (APL). For

patients who develop fever and/or dyspnea following differentiation induction for APL, oxygen saturation should be

assessed and a chest radiograph obtained. Funduscopic examination may demonstrate papilledema from brain

swelling this is a medical emergency.

The differentiation syndrome is a clinical diagnosis based upon a constellation of findings within the context of

remission induction treatment of APL, most commonly with all-trans retinoic acid (ATRA) orarsenic trioxide (ATO).

Any three or more of the following s igns in the absence of other c auses are sufficient to make the diagnosis and

institute glucocorticoids [1,2]:

Fever

Weight gain (from capillary leak and soft tissue edema)

Respiratory distress

Radiographic opacities

Pleural or pericardial effusionHypotension

Renal failure (usually from hypotension, although disseminated intravascular coagulation may also be

present)

The majority of patients will have a combination of dyspnea, fever, and radiographic opacities. (See 'Symptoms and

signs' above.)

Pulmonary hemorrhage is a rare complication of the differentiation syndrome [22]. As glucocorticoid therapy and

transfusions are the main treatments, an invasive procedure is not usually warranted to make this diagnosis. (See

'Bronchoscopy and bronchoalveolar lavage' above.)

A rapid improvement in respiratory status with initiation of glucocorticoids supports the diagnosis of differentiationsyndrome. A lung biopsy is rarely needed, unless the patient fails to improve and noninvasive studies are

unrevealing.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of the differentiation syndrome includes lung infection,

sepsis, thromboembolism, and heart failure. Occasional patients may have a combination of these processes, and

the documented presence of one of them does not exclude a concurrent cytokine release syndrome in APL.

Lung infection The presence of concomitant fever and leukocytosis in patients who are immunosuppressed

requires the exclusion of infectious causes, such as pneumonia due to nosocomial and opportunistic organisms.
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The evaluation should include peripheral blood cultures, sputum smear and culture, and often flexible fiberoptic

bronchoscopy with bronchoalveolar lavage. (See "Approach to the immunocompromised patient with fever and

pulmonary infiltrates".)

Thromboembolism Patients with APL have an increased risk of thrombotic events, including pulmonary

thromboembolism, although the incidence of differentiation syndrome is much greater [ 29,30]. Pulmonary embolism

should be suspected in patients with evidence of peripheral thrombosis and in those with hypoxemia that is out of

proportion to the extent of the radiographic opacities. A computed tomography pulmonary angiogram would typically

be used to exclude this diagnosis. (See "Diagnosis of acute pulmonary embolism".)

Heart failure Measurement of brain natriuretic peptide (BNP) and echocardiography may be helpful in evaluating

left ventricular function. The echocardiogram would also identify a pericardial effusion, if present. (See "Natriuretic

peptide measurement in heart failure" and "Evaluation of the patient with suspected heart failure", section on

'Echocardiography'.)

TREATMENT

General approach Without glucocorticoid treatment, patients treated with all-trans retinoic acid (ATRA) or

arsenic trioxide (ATO) who develop the differentiation syndrome have a mortality rate as high as 30 percent,

principally from hypoxemic respiratory failure or from brain edema. With treatment, most patients demonstrate

improvement within 12 hours and complete resolution of symptoms within 24 hours, although approximately 5percent will not survive [2,7,31].

Our approach to the treatment of differentiation syndrome depends partially upon the severity of the symptoms.

For all patients with suspected differentiation syndrome, we recommend prompt treatment with

glucocorticoids. We typically use intravenous dexamethasone 10 mg twice daily. The dexamethasone is

continued for at least 3 days and until the complete disappearance of symptoms and then tapered. The

syndrome may recur after the glucocorticoids are discontinued, but this is not common.

For most patients with differentiation syndrome, we also suggest the continued administration of the

implicated differentiating agent (ATRA or ATO), rather than its discontinuation.

For patients with severe differentiation syndrome (eg, patients who develop progressive renal failure or

respiratory distress), we also suggest discontinuation of the differentiating agent (ATRA or ATO). Once the

symptoms of differentiation syndrome are completely resolved, the differentiating agent is restarted.

Cytotoxic chemotherapy (eg, cytarabine and an anthracycline) is typically initiated one to three days after

initiation of ATRA however, patients with hyperleukocytosis (eg, WBC 30,000 to 50,000/microL [30 to 50

x10(9)/L]) may benefit from simultaneous initiation of ATRA and cytotoxic therapy [32,33]. (See

"Hyperleukocytosis and leukostasis".)

This approach is consistent with that advocated by both the National Comprehensive Cancer Network (NCCN) and

the European Leukemia Network [5,34,35]. The data to support this treatment approach are presented in thefollowing sections.

Glucocorticoids The use of glucocorticoids in the treatment of differentiation syndrome is largely based upon

clinical experience and data from case series [6,25,36,37]. We recommend prompt treatment with glucocorticoids

for all patients with suspected differentiation syndrome and typically use intravenous dexamethasone 10 mg twice

daily. The dexamethasone is continued for at least 3 days and until the complete disappearance of symptoms and

is then tapered. This recommendation is largely based on the following observations:

In a series of 44 patients with differentiation syndrome, intravenous dexamethasone was initiated at a dose of 10
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mg twice daily in all but two patients [ 7]. All-trans retinoic acid (ATRA) was discontinued at the earliest signs or

symptoms of the differentiation syndrome in 82 percent in that study. The following results were noted:

Two deaths occurred that were attributable to the differentiation syndrome. One of these patients did not

receive dexamethasone until three days after the onset of symptoms the other had prompt administration of

dexamethasone.

The syndrome resolved in all eight patients continued on ATRA with the addition of glucocorticoids.

None of the patients who subsequently received ATRA as maintenance therapy developed differentiation

syndrome.

Retrospective comparisons have noted a decreased mortality rate after the widespread use of empiric

glucocorticoid therapy compared with no glucocorticoid therapy (approximately 5 versus 30 percent mortality)

[6,25,36,37]. This evidence suggests that high-dose glucocorticoids (eg, dexamethasone 10 mg every 12 hours)

are beneficial and has made it impossible to conduct a placebo-controlled trial [ 1,2,7]. However, some patients will

have progression of their symptoms despite dexamethasone administration [38].

The potential toxicities of short-term glucocorticoid treatment include hyperglycemia, insomnia, depression,

emotional instability, and immunosuppression. Severe toxicity is rare.

Differentiation agents It is unclear whether the differentiation agents, all-trans retinoic acid (ATRA) orarsenic

trioxide (ATO), should be continued or discontinued when differentiation syndrome develops. Based on the

retrospective study of 44 patients described above and our clinical experience, it seems likely that ATRA and/or

ATO can be safely continued for most patients with differentiation syndrome as long as prompt treatment with

glucocorticoids is implemented [7]. (See 'Glucocorticoids' above.)

While ATRA and ATO are clearly implicated in the pathogenesis of the syndrome, they are an essential component

of the curative treatment for acute promyelocytic leukemia (APL). It is clear that patients with APL who receive

both ATRA and chemotherapy have superior rates of complete remission and disease-free survival when compared

with patients who receive chemotherapy alone. This is discussed in more detail separately. (See "Initial treatment

of acute promyelocytic leukemia in adults", section on 'ATRA plus chemotherapy'.)

Many clinicians will stop the ATRA and/or ATO if the differentiation syndrome symptoms are severe (eg,

requirement for high-flow oxygen or mechanical ventilation). This practice is largely based upon theoretical

concerns regarding the pathogenesis of differentiation syndrome, which may not be correct.

When ATRA is discontinued due to severe manifestations of the differentiation syndrome, it may be resumed once

manifestations of the differentiation syndrome have resolved. In a retrospective series, differentiation syndrome

recurred in 3 of the 19 patients in whom ATRA was discontinued and then reintroduced two of the three were taking

concurrent glucocorticoids [7]. One death occurred due to recurrent differentiation syndrome.

Once patients have obtained a complete remission, ATRA can be incorporated into the consolidation and

maintenance programs without recurrence of the differentiation syndrome [7,25].


implicated differentiating agent (ATRA or ATO) rather than its discontinuation.

For patients with severe differentiation syndrome (eg, patients who develop renal failure or require admission

to the intensive care unit due to respiratory distress), we also suggest transient discontinuation of the

differentiating agent (ATRA or ATO). Once the symptoms of differentiation syndrome are completely

resolved, the differentiating agent is restarted.
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Supportive care Patients with the differentiation syndrome often require specialized, symptom-directed

supportive care including empiric antibiotics, cautious diuresis, supplemental oxygen, and sometimes, mechanical

ventilation for respiratory failure.

The majority of these patients will have a fever in the setting of immunosuppression requiring the prompt

administration of broad-spectrum antibiotics and a rigorous evaluation for superimposed infection. (See

"Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell

transplant recipients (high-risk patients)" and "Diagnostic approach to the adult presenting with neutropenic

fever".)

An attempt may be made t o diurese the patient as tolerated by hemodynamic and renal status in some

cases this has led to rapid improvement [39]. For patients with renal dysfunction related to hypotension,

renal perfusion should be supported with red blood cell transfusion and/or vasopressors, as indicated.

Many patients will require supplemental oxygen and some will need additional ventilatory support with

noninvasive positive pressure ventilation. Patients with severe respiratory compromise will need intubation

and mechanical ventilation. In one series, mechanical ventilation was needed by 26 percent [ 7]. (See

"Overview of mechanical ventilation".)

Other modalities Other treatment modalities have not proven beneficial. While leukapheresis may blunt the

leukocytosis associated with retinoic acid administration, this procedure is not recommended because of its

potential to worsen the coagulopathy in patients with acute promyelocytic leukemia (APL) and lead to catheter

related thromboses [1,8].

PREVENTION Given the potential severity of differentiation syndrome among patients with acute promyelocytic

leukemia (APL) treated with all-trans retinoic acid (ATRA) orarsenic trioxide (ATO), there has been interest in

whether prophylactic glucocorticoids should be administered either to all patients with APL or to a select group at

higher risk for differentiation syndrome. Based on the following data, we suggest treatment of suspected

differentiation syndrome when symptoms develop rather than the use of prophylactic glucocorticoids.

A single arm prospective study examined the use of prophylactic prednisone (75 mg/day) in 87 patients with APL

and a white blood cell count above 10,000/microL (10 x 10(9)/L) [40]. Differentiation syndrome developed in 16percent of cases with a 3 percent mortality rate.

A retrospective analysis of two prospective studies, one that administered prophylactic prednisone (0.5 mg/kg

daily) and one that did not, reported similar rates of differentiation syndrome [ 41]. An "indeterminant" differentiation

syndrome was present in 23 and 26 percent of those that did or did not receive prophylaxis, respectively. A

"definite" differentiation syndrome occurred in 4 and 5 percent, respectively.

Despite the absence of scientific data, some experts administer prophylactic dexamethasone, 10 mg intravenously

twice daily, to patients with a white blood cell count over 30,000/microL (30 x 10(9)/L) [ 32,33,40].

A prospective, randomized trial of glucocorticoid prophylaxis is required to determine whether this approach

decreases the incidence of mortality associated with differentiation syndrome.

SUMMARY AND RECOMMENDATIONS The differentiation syndrome (previously "retinoic acid syndrome" or

cytokine release syndrome) is a potentially fatal complication of induction chemotherapy in patients with acute

promyelocytic leukemia (APL) characterized by fever, peripheral edema, radiographic pulmonary opacities,

hypoxemia, respiratory distress, hypotension, renal and hepatic dysfunction, and serositis resulting in pleural and

pericardial effusions.

The differentiation syndrome occurs in approximately 25 percent of patients with APL during induction therapy that

includes all-trans retinoic acid (ATRA) orarsenic trioxide (ATO). (See 'Epidemiology' above.)
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For all patients with suspected differentiation syndrome, we recommend prompt treatment with

glucocorticoids, rather than waiting for diagnostic confirmation (Grade 1C). We typically use intravenous

dexamethasone 10 mg twice daily. The dexamethasone is continued until the complete disappearance of

symptoms and then tapered. (See 'Glucocorticoids' above.)


implicated differentiating agent (ATRA or ATO), rather than its discontinuation (Grade 2C). (See

'Differentiation agents' above.)

For patients with severe manifestations of differentiation syndrome (eg, requirement for high-flow oxygen or

mechanical ventilation), we suggest temporary discontinuation of the differentiating agent (ATRA or ATO)

until the patient is stable, rather than continuation (Grade 2C). Once the symptoms of differentiation

syndrome are completely resolved, the differentiating agent is restarted. (See 'Differentiation agents' above.)

For most patients with APL, we suggest treatment of suspected differentiation syndrome when symptoms

develop, rather than the use of prophylactic glucocorticoids (Grade 2C). Patients with hyperleukocytosis

(white blood cell count over 30,000/microL) may have a lower risk of differentiation syndrome when given

prophylactic dexamethasone 10 mg twice daily intravenously. (See 'Prevention' above.)

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GRAPHICS

Chest CT scan of alveolar hemorrhage in differentiationsyndrome

Axial (A) and coronal (B) CT chest images from a patient with thedifferentiation syndrome. Bronchoalveolar lavage showed alveolarhemorrhage.Courtesy of German Pihan, MD, Department of Pathology, Beth Israel Deaconess Medical

Center, Boston, MA.


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Bronchoalveolar lavage of alveolar hemorrhage in thedifferentiation syndrome

Bronchoalveolar lavage from a patient with differentiation syndrome andalveolar hemorrhage. Image A shows an alveolar macrophage ringed byacute promyelocytic leukemia (APL) cells on a background of erythrocytes.Image B shows two alveolar macrophages ingesting erythrocytes on abackground of erythrocytes and scattered APL cells. The presence oferythrocytes within the alveolar macrophages suggests alveolar

hemorrhage rather than acute trauma at the time of bronchoscopy. TheAPL cells are present in the BAL due to the degree of hemorrhage.Courtesy of German Pihan, MD, Department of Pathology, Beth Israel Deaconess Medical

Center, Boston, MA.

Differentiation (Retinoic Acid) Syndrome

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