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A 56-Year-Old Man With Acute Promyelocytic Leukemia and Pulmonary InfiltratesAcute Leukemia and Pulmonary Infiltrates FREE TO VIEW

David C. Weir, MD; Jennifer Y. Fung, MD; Sidney S. Braman, MD, FCCP
Author and Funding Information

From the Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

CORRESPONDENCE TO: Sidney S. Braman, MD, FCCP, Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1232, New York, NY 10029; e-mail: sidney.braman@mssm.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(3):e88-e91. doi:10.1378/chest.14-0283
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A 56-year-old man presented to the ED of an outside hospital with 2 days of bleeding gums and easy bruising. He denied episodes of melena, hematemesis, or hematuria and had no epistaxis. Routine blood work showed pancytopenia and evidence of diffuse intravascular coagulation. A bone marrow biopsy confirmed the diagnosis of acute promyelocytic leukemia. He was transferred to our hospital for treatment.

He had no medical history and was unaware of any familial medical problems. He did not drink alcohol and had never used tobacco products. He was originally from Haiti and had been working as a mental health worker for the previous 23 years.

On admission to the hospital, he received cryoprecipitate, platelet transfusion, and prophylactic antibiotics. For the leukemia, he was started on all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). After initiation of therapy for acute promyelocytic leukemia (APML), he developed nightly fevers up to 38.9°C despite treatment with acyclovir, voriconazole, cefepine, and vancomycin. All cultures were negative. On hospital day 7 he became tachycardic and hypoxemic, with increasing dyspnea on exertion, orthopnea, and a dry cough.

Physical Examination Findings

On admission, the patient was afebrile, with a pulse of 100 beats/min, BP of 124/71 mm Hg, a respiratory rate of 17 breaths/min, and oxygen saturation of 100% on room air. His weight was 76 kg. Both cardiac and lung examinations were normal, and he had no peripheral edema.

On hospital day 7, he was febrile and tachycardic to 120/min. His weight was 83 kg. His oxygen saturation on room air was 80%. He required supplemental oxygen via nasal cannula to maintain a saturation above 90%. Pertinent positive findings included bilateral rhonchi, primarily in the lower lung fields, and 2+ symmetric lower-extremity edema. The rest of his physical examination was unchanged.

Diagnostic Studies

On admission, WBC count was 3,300/μL, hemoglobin level was 8.1 G/dL, and platelet counts were 17,000/μL. The differential count on the WBC was 7% segmental cells, 4% bands, 30% blasts, 1% metamyelocytes, and 5% myelocytes. His D-dimer level was > 20 μg/mL (< 0.05 μg/mL), fibrinogen was 52 mg/dL (175-450 mg/dL), and international normalized ratio was 1.6. He had a normal basic metabolic panel. An admission chest radiograph and an echocardiogram were normal.

On day 7, the WBC count was 10,500/μL with a differential of 5% segmental cells, 4% bands, 3% blasts, 32% metamyelocytes, and 20% myelocytes. The D-dimer level was 3.7 μg/mL, his fibrinogen was 242 mg/dL, and international normalized ratio was 1.2. A repeat chest radiograph was performed (Fig 1), followed by a CT angiographic scan of the chest (Fig 2).

Figure Jump LinkFigure 1  Chest radiograph showing small right pleural effusion with blunting of the right costophrenic angle. Patchy opacities are seen throughout the right lung, predominantly within the right upper lobe, as well as, to a lesser degree, within the left upper lobe.Grahic Jump Location
Figure Jump LinkFigure 2  CT scan of the chest. A, Patchy ground-glass, nodular, and consolidative opacities throughout the right lung and within the left upper lobe. B, Small right pleural effusion. Trace left pleural effusion.Grahic Jump Location
What is the diagnosis?
Diagnosis: Differentiation syndrome (ATRA syndrome) in promyelocytic leukemia

The majority of cases of APML are characterized by a balanced reciprocal translocation of chromosomes 15 and 17. The retinoic acid receptor α (RARα) on chromosome 17 and the promyelocytic leukemic protein on chromosome 15 are joined to create the oncoprotein PML-RARα. The wild-type function of the RARα gene leads to gene repression in the absence of retinoic acid and gene transcription (differentiation) in the presence of retinoic acid. The fusion protein PML-RARα does not respond to physiologic levels of retinoic acid and, therefore, differentiation and programed cell death do not occur.

Current treatment of APML consists of a combination of ATRA with anthracycline-containing chemotherapy, or, as with this patient, ATO. With the introduction of ATRA in the late 1980s for the treatment of APML, remission rates of > 90% and cure rates of approximately 80% have been achieved. Rather than the cytotoxic effects of chemotherapy, ATRA induces differentiation of promyelocytes into phenotypically mature myelocytes, leading to a “normal” programmed cell death. In 1992, a constellation of complications was recognized in patients with APML being treated with ATRA induction therapy, and this was termed the “retinoic acid syndrome.” It may be seen in up to 25% of patients receiving ATRA therapy. Subsequently, ATO has also been associated with this syndrome and with a similar frequency.

The ATRA syndrome, now commonly referred to as differentiation syndrome (DS), is a distinct clinical entity. This patient had many features of DS: unexplained fever, dyspnea, weight gain of > 5 kg, peripheral edema, pleural effusions, and interstitial infiltrates. Other features may include unexplained episodic hypotension and peripheral edema, pericardial effusion, and renal failure. The signs and symptoms of this syndrome are commonly encountered in hospitalized patients with hematologic malignancy; therefore, other causes must be ruled out before the diagnosis of DS can be made. This includes an assessment for congestive heart failure and cardiac disease, sepsis, diffuse alveolar hemorrhage, other pneumonias or infections, and other causes of renal failure. The radiographic abnormalities of DS are listed in Table 1.

Table Graphic Jump Location
TABLE 1  ] Clinical and Radiographic Features of Differentiation Syndrome

The development of DS in most patients being treated with ATRA occurs in a bimodal distribution. Severe DS, defined as four or more signs or symptoms (Table 1), occurs more commonly within the first week, and moderate DS (two to three signs or symptoms) tends to occur more commonly during the third week of therapy.

It is thought that ATRA-induced cell differentiation causes an intense inflammatory response and that this results in an abnormal release of chemokines, cytokines, and adhesion molecules. This may result in an extravasation of fluids that would explain many of the clinical findings. In patients who have been given a diagnosis of DS, treatment consists of initiation of corticosteroid therapy and supportive care for volume overload and respiratory failure. Prophylaxis of DS with corticosteroids is controversial but it has been recommended by some for patients with WBC counts > 10,000/μL. In patients who develop DS, the recommended treatment is dexamethasone at a dose of 10 mg bid for 3 to 5 days, then tapering over a 2-week period. In milder cases and when therapy proves effective, ATRA or ATO can be continued. However, in severe cases (respiratory or acute renal failure), discontinuation is recommended until recovery.

APML is characterized by its aggressive nature and the rapid development of severe coagulopathies. Fatal hemorrhage, usually intracranial or pulmonary, continues to be the most common cause of death despite supportive therapies directed at coagulation abnormalities and prompt initiation of ATRA therapy. In patients who develop severe DS, ARDS and alveolar hemorrhage-related mortality may occur. Patients with severe DS also require more transfusions, mechanical ventilation, and dialysis. Factors that predict the development of moderate to severe DS include WBC count > 10,000/μL, lactate dehydrogenase greater than the upper limit of normal, elevated creatinine, FMS-related tyrosine kinase 3 with internal tandem duplication (FLT3-ITD) mutation, PML-RARα isoform, and male sex. Currently, it is unclear if the development of DS affects relapse-free survival.

Clinical Course

IV dexamethasone at 10 mg bid was started following the discovery of the radiographic opacities. It was continued for 5 days, followed by prednisone for 10 days. Within 24 h, he showed a marked clinical improvement. His dyspnea and fever resolved, and his oxygen saturation normalized. However, radiographic improvement lagged by several weeks. He continued his ARTA/ATO therapy and was discharged from the hospital after a bone marrow biopsy on hospital day 40 showed complete remission.

  • 1. Current combination therapy of APML includes ATRA. This induces differentiation of promyelocytes into phenotypically mature myelocytes, leading to a “normal” programmed cell death.

  • 2. During induction therapy with ATRA regimens, up to 25% of patients will develop a potentially life-threatening DS, formerly called ATRA syndrome.

  • 3. Clinical features of DS may include unexplained fever, weight gains of > 5 kg, peripheral edema, pericardial or pleural effusions, dyspnea, unexplained episodic hypotension, and renal failure.

  • 4. Common radiographic features of DS include pleural effusion, cardiomegaly, increased vascular pedicle width, interstitial infiltrates, pulmonary vascular congestion, and interstitial and alveolar edema.

  • 5. IV dexamethasone is an effective treatment of DS. In severe cases (respiratory or acute renal failure), it is recommended that ATRA and ATO be discontinued until recovery.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contribution:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell RP Jr. The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann Intern Med. 1992;117(4):292-296. [CrossRef] [PubMed]
 
Jung JI, Choi JE, Hahn ST, Min CK, Kim CC, Park SH. Radiologic features of all-trans-retinoic acid syndrome. AJR Am J Roentgenol. 2002;178(2):475-480. [CrossRef] [PubMed]
 
Montesinos P, Bergua JM, Vellenga E, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-transretinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood. 2009;113(4):775-783. [CrossRef] [PubMed]
 
Montesinos P, Sanz MA. The differentiation syndrome in patients with acute promyelocytic leukemia: experience of the pethema group and review of the literature. Mediterr J Hematol Infect Dis. 2011;3(1):e2011059. [PubMed]
 
Lo-Coco F, Avvisati G, Vignetti M, et al; Gruppo Italiano Malattie Ematologiche dell’Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111-121. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1  Chest radiograph showing small right pleural effusion with blunting of the right costophrenic angle. Patchy opacities are seen throughout the right lung, predominantly within the right upper lobe, as well as, to a lesser degree, within the left upper lobe.Grahic Jump Location
Figure Jump LinkFigure 2  CT scan of the chest. A, Patchy ground-glass, nodular, and consolidative opacities throughout the right lung and within the left upper lobe. B, Small right pleural effusion. Trace left pleural effusion.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1  ] Clinical and Radiographic Features of Differentiation Syndrome

Suggested Readings

Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell RP Jr. The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann Intern Med. 1992;117(4):292-296. [CrossRef] [PubMed]
 
Jung JI, Choi JE, Hahn ST, Min CK, Kim CC, Park SH. Radiologic features of all-trans-retinoic acid syndrome. AJR Am J Roentgenol. 2002;178(2):475-480. [CrossRef] [PubMed]
 
Montesinos P, Bergua JM, Vellenga E, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-transretinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood. 2009;113(4):775-783. [CrossRef] [PubMed]
 
Montesinos P, Sanz MA. The differentiation syndrome in patients with acute promyelocytic leukemia: experience of the pethema group and review of the literature. Mediterr J Hematol Infect Dis. 2011;3(1):e2011059. [PubMed]
 
Lo-Coco F, Avvisati G, Vignetti M, et al; Gruppo Italiano Malattie Ematologiche dell’Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111-121. [CrossRef] [PubMed]
 
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