Bullous Sweet Syndrome in a Patient With t(9;22)(q34;q11)-Positive Chronic Myeloid Leukemia Treated With the Tyrosine Kinase Inhibitor Nilotinib: Interphase Cytogenetic Detection of BCR-ABL– Positive Lesional Cells

Background  An association of Sweet syndrome with chronic myeloid leukemia (CML) has been recently observed in patients treated with tyrosine kinase inhibitors.

Observations  We describe a 67-year-old patient with a 6-year history of Philadelphia chromosome translocation t(9;22)(q34;q11)-positive CML. The tyrosine kinase inhibitor AMN107 (nilotinib) kept the patient in chronic phase. After 10 months of taking nilotinib, he developed pneumonia with septic features. Seven days later, bullous skin infiltrations on the upper arms and a large, painful bullous swelling of the right neck occurred without any evidence of a viral, bacterial, or fungal blood infection. Findings from histologic examination showed massive infiltrations of the whole dermis with neutrophil granulocytes as well as with monocytoid histiocytic cells. Fluorescence in situ hybridization analysis of paraffin-embedded tissue revealed a BCR-ABL fusion, indicating the presence of t(9;22)(q34;q11). The addition of oral prednisolone to an adequate antibiotic treatment led to rapid resolution of the cutaneous infiltrations.

Conclusions  Skin infiltrations consistent with Sweet syndrome can occur in patients with septic CML during the treatment with tyrosine kinase inhibitors, including nilotinib. Skin infiltrations can include specific CML cells.

Sweet syndrome (SS), also referred to as acute febrile neutrophilic dermatosis, is a rare skin disease characterized by the triad of fever, leucocytosis, and erythematous plaques infiltrated with neutrophils.¹ The onset is often associated with an infection—for instance, of the upper respiratory tract or gastrointestinal tract—but can also be drug induced or appear as a paraneoplastic syndrome in hematologic malignant neoplasms such as chronic myeloid leukemia (CML).²

Over the past few years, molecularly targeted therapies were developed to treat neoplasms more specifically than with conventional chemotherapy. The tyrosine kinase inhibitor imatinib mesylate (STI571 [signal transduction inhibitor number 571], Gleevec or Glivec [outside of the United States]; Novartis Pharmaceuticals Corp, East Hanover, NJ) is a selective inhibitor of the BCR-ABL kinase in Philadelphia chromosome (Ph) t(9;22)(q34;q11)-positive chronic myeloid leukemia.³ As patients with CML become increasingly resistant to imatinib, novel tyrosine kinase inhibitors with higher binding affinities to BCR-ABL such as AMN107 (nilotinib) have been developed within the last few years.⁴

We describe herein a man with Ph translocation t(9;22)(q34;q11)-positive CML, who developed bullous SS while receiving treatment with the new tyrosine kinase inhibitor nilotinib.

A 67-year-old patient presented with a 6-year history of Ph translocation–positive CML. The karyotype was 46,XY, t(9;22)(q34;q11). Previous treatments included interferon alfa, hydroxyurea, as well as an opposing field irradiation of the right shoulder. Due to CML progression without any further chromosomal aberrations in addition to the Ph translocation t(9;22)(q34;q11), the therapy was changed to the tyrosine kinase inhibitor imatinib. After a 4-year period of stable disease while receiving imatinib treatment, the patient developed a blast crisis. Therefore, the therapy was switched to the more selective tyrosine kinase inhibitor nilotinib (400 mg twice daily), which shifted the disease back to the chronic phase. However, this new therapeutic approach was associated with neutrocytopenia and thrombocytopenia. After approximately 10 months of nilotinib treatment, he developed pneumonia including pleural effusion and septic temperatures up to 40°C. Despite the cessation of nilotinib therapy and initial management with the antibiotics meropenem and vancomycin, his state of health did not improve. Subsequently, bullous skin infiltrations on the upper arms and the left hip as well as a large painful bullous swelling of the right neck with loss of contours occurred after 1 week (Figure 1).

A hemogram showed pancytopenia with an erythrocyte count of 2.4 × 10⁶/μL (to convert to × 10¹²/L, multiply by 1.0), a platelet count of 15.7 × 10³/μL (to convert to × 10⁹/L, multiply by 1.0), and a total leukocyte count of 1300/μL (to convert to × 10⁹/L, multiply by 0.001). The differential blood cell count revealed an increase of band neutrophils (15%) and C-reactive protein level was elevated above 200 mg/L. Laboratory investigations revealed no active viral (varicella-zoster virus, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, hepatitis B virus, hepatitis C virus, or human immunodeficiency virus) or fungal (Aspergillus or Candida) blood infections. Bacterial blood cultures were negative. Stool cultures showed no evidence of viral (rotavirus, adenovirus, or norovirus), fungal (yeasts), or bacterial (Clostridium difficile, Salmonella, Shigella, Yersinia, or Campylobacter) infections. An infection with Enterococcus faecalis could be detected in pharyngeal smears and in bronchoalveolar lavage fluid. There were no additional infections (enterovirus, human herpesvirus 6, herpes simplex virus, varicella-zoster virus, respiratory syncytial virus, parainfluenza virus, adenovirus, influenza virus, mycoplasma, Legionella infection, mycobacterium tuberculosis infection, or Pneumocystitis carinii infection) or tumor cells. The pneumonia was confirmed by a chest radiograph and computed tomographic scan indicating infiltrates in the right middle lobe and the lower lobes as well as a pleural effusion. Findings from abdominal ultrasonography were normal except for mild splenomegaly.

Indirect immunofluorescence performed on commercial cryostat sections of monkey esophagus (The Binding Site, Birmingham, England) revealed no serum antibodies that would indicate a bullous autoimmune disease. Results from polymerase chain reaction tests from lesional skin biopsy specimens were negative for herpes simplex virus type 1 and type 2, varicella-zoster virus, and human papillomaviruses.

Histologic examination of a skin biopsy specimen from the right neck revealed massive dermal infiltrates consisting mostly of neutrophil granulocytes, with admixed monocytoid histiocytic cells also spreading into the spongiotic epidermis. In addition, atypical monocytoid cells showing vesicular nuclei with enlarged nucleoli and binuclear cells were present. These cells are usually not found in classic SS. Furthermore, large areas of hemorrhage within the infiltrated dermis were evident. Immunohistochemical analysis with CD68 antibody highlighted the histiocytic cells (Figure 2).

To differentiate between reactive cells and specific CML cells within the skin infiltrates, we performed fluorescence in situ hybridization to identify Ph translocation t(9;22)(q34;q11)-positive CML cells.⁵ In brief, pretreated paraffin-embedded lesional tissue sections were hybridized with a directly labeled, dual-color, dual-fusion probe for the translocation t(9;22)(q34;q11) (LSI BCR/ABL Dual Color, Dual Fusion Probe; Abbott/Vysis, Downers Grove, Illinois).⁶ Fluorescence in situ hybridization analysis revealed a BCR-ABL gene (OMIM 151410) fusion indicating the presence of the t(9;22)(q34;q11) translocation in a significant number of infiltrating cells. This demonstrates that the skin infiltrates contain specific CML cells in a considerable amount in addition to unspecific infiltrating inflammatory cells (Figure 2).

Clinically, the addition of prednisolone, 1 mg/kg daily, to an adequate antibiotic treatment led to rapid resolution of the cutaneous bullous infiltrations, and no further blisters occurred (Figure 1). After that episode, nilotinib therapy was continued, no further skin lesions appeared, and the patient remained in the chronic phase of CML.

In 1964 Robert Douglas Sweet¹ described “an acute febrile neutrophilic dermatosis” for the first time. This so-called SS is characterized by tender painful erythematous papules and plaques, acute onset of fever, and peripheral leukocytosis with neutrophilia.² In addition, systemic symptoms like malaise, myalgia, or arthralgia can occur.⁷ Predilection sites for skin lesions are the head, the neck, and the upper extremities. Sweet syndrome can occur in all races and ages. Predominantly, women aged between 30 and 50 years are affected. The onset of SS is often related to an infectious trigger, for example, an infection of the upper respiratory tract or gastrointestinal tract. However, SS can also be associated with drugs, autoimmune disease, vaccination, or pregnancy. In about 20% of all cases, SS is associated with malignant neoplasms. In 85% of these cases an underlying hematological malignant lesion is evident, mostly acute myeloid leukemia.⁸ However, the association of SS with CML is also well documented.^9,10

Our 67-year-old patient with CML presented with bullous skin lesions on the typical localizations for SS, the neck and upper extremities. This is in line with several reports that severe bullous SS skin lesions are often associated with an underlying malignant neoplasm.^11-13

Sweet syndrome can occur in various phases of the CML. A potential association with disease progression has been controversially discussed.^14,15 Our patient had no disease progression and showed no signs of a blast crisis in the peripheral blood at the time of SS development.

The Ph translocation t(9;22)(q34;q11) leads to the chimeric BCR-ABL fusion protein and a constitutively active tyrosine kinase that initiates leukemic transformation.^16,17 The tyrosine kinase inhibitor imatinib is a selective inhibitor of this BCR-ABL kinase and became the first choice of treatment for all patients with newly diagnosed CML.³ In our case, imatinib treatment kept the patient in a stable chronic phase for 4 years.

Recently, an association between the tyrosine kinase inhibitor imatinib and the occurrence of SS has been reported. Ayirookuzhi et al¹⁸ described an African American woman who developed SS soon after application of imatinib on 2 separate occasions. In a similar case, tender nodular skin lesions consistent with SS occurred in a patient with CML 10 months after the start of imatinib treatment.¹⁹

Because of increasing imatinib resistance related to point mutations affecting the tyrosine kinase domaine of the chimeric BCR-ABL protein or BCR-ABL amplifications²⁰ novel tyrosine kinase inhibitors have been developed. In our patient, the therapy was switched to nilotinib, which exhibits a 20-fold stronger binding affinity to BCR-ABL compared with imatinib.⁴ In the largest series published to date analyzing the safety profile of nilotinib in 119 patients with imatinib-resistant CML and acute lymphoblastic leukemia, myelosuppression, transient indirect hyperbilirubinemia, and skin rashes were the most common adverse effects.²¹ The skin reactions included dry skin and pruritus. No further skin symptoms resembling SS were described.

Histologically, cutaneous lesions of SS typically comprise dermal infiltrates of mature neutrophils sparing the epidermis. In our case, the cells also spread into the spongiotic epidermis, a sign frequently observed in SS associated with underlying malignant neoplasms. Recent case reports demonstrated leukemic cells within the skin infiltrate in patients with CML using fluorescence in situ hybridization¹⁹ or polymerase chain reaction techniques²² on lesional tissue. We were able to identify the BCR-ABL fusion indicating the Ph translocation t(9;22)(q34;q11) in a significant number of infiltrating cells, confirming these observations.

It is assumed that malignant leukemic cells—recruited to the skin due to specific tissue homing—sustain the SS.²³ On the other hand, it has been supposed that the CML cells are only innocent bystanders attracted by the inflammatory process in the context of the SS.²² Another hypothesis that may explain the coexistence of CML with SS deals with the fact that granulocyte-colony stimulating factor, which is capable of enhancing the neutrophilic maturation and mobilization, could induce a differentiation of the primary CML cells to mature neutrophils.²⁴ However, no granulocyte-colony stimulating factor treatment was given to our patient. In a patient with CML, described as Ph t(9;22)(q34;q11) negative, Watari et al²⁵ reported a hypersensitivity of the malignant bone marrow cells to granulocyte-colony stimulating factor already at a physiological level. This led to an increased peripheral interleukin 8 production, which induced chemotaxis of neutrophils to the skin. If the identified CML cells in the skin infiltrate sustained the SS in our patient or were mere bystanders remains unclear.

In conclusion, skin infiltrations consistent with SS can occur during the treatment with the classic tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec or Glivec) as well as during the application of the new tyrosine kinase inhibitor AMN107 (nilotinib). In patients with CML, the skin infiltrations can comprise both reactive infiltration and specific CML cell infiltration.

Correspondence: Steffen Emmert, MD, Department of Dermatology, Georg-August-University Goettingen, Von-Siebold-Strasse 3, 37075 Goettingen, Germany (semmert@gwdg.de).

Accepted for Publication: May 5, 2007.

Author Contributions: Drs Kaune and Emmert had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kaune, Neumann, and Emmert. Acquisition of data: Kaune, Baumgart, Gesk, Baesecke, Glass, Siebert, Ghadimi, Neumann, and Emmert. Analysis and interpretation of data: Kaune, Baumgart, Gesk, Mitteldorf, Glass, Haase, Siebert, Ghadimi, and Emmert. Drafting of the manuscript: Kaune, Neumann, and Emmert. Critical revision of the manuscript for important intellectual content: Baumgart, Gesk, Mitteldorf, Baesecke, Glass, Haase, Siebert, and Neumann. Administrative, technical, and material support: Kaune, Baumgart, Gesk, Mitteldorf, Baesecke, Glass, Haase, Siebert, Ghadimi, Neumann, and Emmert. Study supervision: Kaune, Glass, Siebert, Ghadimi, Neumann, and Emmert.

Financial Disclosure: None reported.