When the treatment becomes the problem

Sonia M. Castillo MDMark Hamblin MD, FCCP

Department of Internal MedicineUniversity of Kansas Medical Center, Kansas City

Background

Melanoma: 5th most prevalent cancer1

First line treatment: local excision

Interferon (IFN) alfa therapy: indicated as adjuvant treatment2

1. Kim KB, Davies MA, Rapini RP, Hwu P, Bedikian AY. Chapter 39. Malignant Melanoma. In: Kantarjian HM, Wolff RA, Koller CA, eds. The MD Anderson Manual of Medical Oncology. 2nd ed. New York: McGraw-Hill; 2011.

2. Ascierto PA, Gogas HJ, Grob JJ et al. Adjuvant interferon alfa in malignant melanoma: an interdisciplinary and multinational expert review. Critial Reviews in Oncology/Hematology. 2013;85:149-161

Case presentation80 year old male with malignant melanoma

09/2011 Shave biopsy of scalp lesion11/2011 Excision and nodal dissection01/2012 Peginterferon alpha 2b12/2012 Shortness of breath for 6 weeks

Past Medical History

Malignant MelanomaHypertension

MedicationsPeginteron alfa-2bAmlodipine

NonsmokerNo petsNo sick contacts

Social History

Physical examTemp=38.2C HR=102 BP=122/58RR=24 SO2=88% on room air

General: Well-developed male in mild respiratory distressCardiovascular: TachycardicRespiratory: Bibasilar fine cracklesExtremities: no clubbing

Chest X-ray

Initial laboratory testingWhite blood cell count: 6.2

Neutrophils: 54%Lymphocytes: 34%Monocytes: 12%

Arterial blood gas: 7.49/30/55/23

B-type natriuretic peptide: 39

Chest CT Angiography

Apices Mid-lung fields

Lung bases

Infectious work-up Bacterial and AFB smear and

culture Legionella urine antigen Mycoplasma IgG and IgM Aspergillus galactomannan Fungitell Histoplasma and coccidioides urine

antigens Cryptococcal serum antigen Respiratory viral panel

Negative

Autoimmune work-up

ANAC-ANCA, P-ANCAAnti GBM Antibody

Negative

Bronchoalveolar lavageCell count:

Red blood cells: 1450/uLWhite blood cells: 360/uL

Monocytes: 55% (Normal>85%1)

Lymphocytes: 29%(Normal=10-15%1)

Neutrophils: 16% (Normal<3%1)

1. Meyer K, Raghu G, Baughman R et al. An Official American Thoracic Society Clinical Practice Guideline: The Clinical Utility of Bronchoalveolar Lavage Cellular Analysis in Interstitial Lung Disease. Am J Respir Crit Care Med Vol 185, Iss. 9, pp 1004–1014, May 1, 2012

Other studies:Bacterial, mycobacterial

and fungal stain and culture

Respiratory viral panelPJP PCRCytology

NEGATIVE

Hospital courseAntibiotics and trial of diuresis

Non-invasive positive pressure ventilation

Unrevealing infectious work-up

Methylprednisolone 125mg IV q6hrs

No response

Discontinuation of antibiotics

Clinical improvement

Follow-up CT chest

2 months later

DiscussionWhy did we suspect IFN-induced interstitial lung disease (ILD) on this patient?

1. Negative work-up for infectious, autoimmune and malignant processes

2. Findings on Chest CT3. Lymphocytosis on BAL cell count4. Clinical deterioration despite empiric

antibiotics

IFN-induced ILD

Uncommon complication (0.01-0.3%)1

Presenting symptoms: dyspnea, dry cough, fever, fatigue, anorexia, myalgias2

Average time of presentation: 12 weeks

1. Solsky J, Liu J, Peng M, Schaerer M, Tietz A. Rate of interstitial pneumonitis among hepatitis virus C infected patients treated with pegylated infeterferon. J Hepatol. 2009; 50 Suppl 1: S238.2. Ji FP, Li ZX, Deng H et al. Diagnosis and management of interstitial pneumonitis associated with interferon therapy for chronic hepatitis C. World Journal of Gastroenterology. 2010;16(35):4394.

Case reports

Diagnosis of IFN-induced ILD1

Exclusion of other etiologies Compatible chest CT Lymphocytosis on BAL cell count Resolution of symptoms and infiltrates

after cessation of therapy

1. Ji F-P. Diagnosis and management of interstitial pneumonitis associated with interferon therapy for chronic hepatitis C. World Journal of Gastroenterology. 2010;16(35):4394.

Treatment of IFN-induced ILD

Discontinuation of IFN

Corticosteroids1

1. Puente Vazquez J, Moreno Anton F, Grande Pulido E, Lopez Tarruella-Cobo S, Perez Segura P, Diaz-Rubio E. Interstitial pneumonitis and lung fibrosis during adjuvant treatment of melanoma with interferon alpha according to the Kirkwood schedule. Dermatology. 2005;210(3):247-249.

Key points

IFN-induced Interstitial Lung Disease:

Uncommon complication of IFN-alfa 2b therapy, but potentially life threatening

Should be a diagnosis of exclusion

Acknowledgements Mark Hamblin MD, FCCP

Division of Pulmonary and Critical CareDepartment of Internal MedicineUniversity of Kansas Medical Center, Kansas City, Kansas

Gary Doolittle MDDivision of Hematology and OncologyDepartment of Internal MedicineUniversity of Kansas Medical Center, Kansas City, Kansas

Questions?

Thank you!

Case reports

IFN-related pulmonary toxicity

Interstitial pneumonitisBOOPARDSPleural effusionAsthma exacerbation

Cases with other malignancies

- Melanoma. Puente Vasquez et al. Dermatology 2005

- Hemangioendotelioma. Wolf et al. Clinical Toxicology 1997

- CML. Yufu et al. American Journal of Hematology 1994