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Figure.
Clinical and Pathologic Findings in FLT3 Inhibitor–Associated Neutrophilic Dermatoses
Clinical and Pathologic Findings in FLT3 Inhibitor–Associated Neutrophilic Dermatoses

A, Red subcutaneous nodules noted on bilateral lower extremities. B, The biopsy specimen reveals a dense, subcutaneous inflammatory infiltrate mainly composed of neutrophils with scattered eosinophils (hematoxylin-eosin, original magnification ×400). C, Nodular eruption on the cheek. D, Low-power view of the biopsy specimen reveals epidermal acanthosis and a brisk dermal, superficial, and deep inflammatory infiltrate (hematoxylin-eosin, original magnification ×40).

Table.  
Clinical Characteristics of the Study Patients
Clinical Characteristics of the Study Patients
1.
Pemmaraju  N, Kantarjian  H, Ravandi  F, Cortes  J.  FLT3 inhibitors in the treatment of acute myeloid leukemia: the start of an era?  Cancer. 2011;117(15):3293-3304.PubMedGoogle ScholarCrossref
2.
Cancer Genome Atlas Research Network.  Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.  N Engl J Med. 2013;368(22):2059-2074.PubMedGoogle ScholarCrossref
3.
Levis  MJ, Perl  AE, Dombret  H,  et al.  Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation.  Blood. 2012;120(21):673.Google Scholar
4.
Perl  A, Altman  J, Cortes  J,  et al. Results of a first in-human, Phase 1/2 trial of ASP2215, a selective, potent oral inhibitor of FLT3/AXL, in patients with relapsed or refractory acute myeloid leukaemia. Paper presented at the 20th Congress of the European Hematology Association; June 11, 2015; Vienna, Austria.
5.
Sexauer  A, Perl  A, Yang  X,  et al.  Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AML.  Blood. 2012;120(20):4205-4214.PubMedGoogle ScholarCrossref
6.
Fathi  AT, Le  L, Hasserjian  RP, Sadrzadeh  H, Levis  M, Chen  YB.  FLT3 inhibitor–induced neutrophilic dermatosis.  Blood. 2013;122(2):239-242.PubMedGoogle ScholarCrossref
Research Letter
April 2016

FLT3 Inhibitor–Associated Neutrophilic Dermatoses

Author Affiliations
  • 1Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 2Department of Pathology, The University of Arizona College of Medicine, Tucson
  • 3Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 4Department of Dermatology and Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 5Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
JAMA Dermatol. 2016;152(4):480-482. doi:10.1001/jamadermatol.2015.6121

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by a disruption in normal hematopoiesis that results in uninhibited myeloblast proliferation. Cutaneous reactions in AML include leukemia cutis, Sweet syndrome, infections, and treatment-related effects. We present 3 cases of FLT3 (OMIM 136351) inhibitor–associated neutrophilic dermatoses (Table).

Methods

Patients with FLT3-positive AML underwent treatment as part of 2 concurrent institutional review board–approved clinical trials. If skin lesions were observed during treatment, a dermatologist evaluated the patient as part of standard of care. The University of Pennsylvania Institutional Review Board approved the clinical trials evaluating FLT3 inhibitors for AML. The patients were seen as part of standard of care evaluation of skin and not as part of their study protocol. These patients provided written informed consent to participate in the FLT3 inhibitor clinical trial; dermatologic evaluation was separate from that trial.

Results

Seventy-seven patients were treated with FLT3 inhibitors for AML; 3 developed confirmed neutrophilic dermatoses. Patient 1 was a woman in her 40s diagnosed as having cytogenetically normal AML complicated by relapsed disease with FLT3 internal tandem duplication (ITD) after induction, consolidation, and stem cell transplantation. Therapy with the FLT3 inhibitor gilteritinib reduced marrow blasts from 80% to 10%. Two months later, the patient developed multiple tender, red subcutaneous nodules on her back and lower extremities (Figure, A) in the absence of progressive leukemia. A skin biopsy revealed neutrophil-predominant lobular panniculitis (Figure, B). The eruption improved with 60 mg/d of prednisone and prolonged taper. She later died of disease progression.

Patient 2 was a man in his 70s diagnosed as having acute erythroleukemia with normal karyotype complicated by relapsed disease with FLT3 ITD after induction. Gilteritinib nearly eliminated peripheral blasts and reduced marrow blasts to 25%. After 2 months, he developed pustulonodules on the cheeks, ears, and scalp (Figure, C). Skin biopsy revealed interstitial neutrophil-rich inflammatory infiltrate and clusters of atypical mononuclear cells (Figure, D). The eruption improved with topical corticosteroids. Gilteritinib treatment was later stopped because of disease progression.

Patient 3 was a woman in her 60s diagnosed as having FLT3 ITD–positive AML refractory to induction and salvage therapy. Quizartinib eliminated circulating blasts and reduced marrow blasts to less than 5%. Two months later, she developed a tender, red eruption on the neck and arms. A skin biopsy revealed perivascular, interstitial, and perieccrine neutrophilic inflammatory infiltrate and subepidermal edema. Clinical manifestations improved with 50 mg/d of prednisone and prolonged taper. Quizartinib treatment was discontinued given concern for possible FLT3 inhibitor–induced differentiation syndrome.

Discussion

The FLT3 gene encodes a receptor tyrosine kinase that, in response to its cytokine ligand, regulates the proliferation, survival, and differentiation of hematopoietic stem cells and early myeloid and lymphoid progenitors.1FLT3 is one of the most commonly mutated genes in AML, affected in 30% of patients.2 The presence of FLT3 ITD carries a poor prognosis because of high relapse rates. Inhibitors of FLT3 have caused significant regression of FLT3-mutated AML in early trials of chemotherapy-refractory patients.3,4 In these trials, patients have had terminal differentiation of leukemia cells to neutrophils during treatment with FLT3 inhibitors; neutrophilic dermatoses have been rarely reported.5,6 This finding may result in a differentiation syndrome similar to that seen in patients with acute promyelocytic leukemia treated with all-trans-retinoic acid. Two of our patients developed symptoms of differentiation syndrome along with Sweet syndrome. Like retinoic acid syndrome, our patients’ symptoms were corticosteroid responsive. Our patients were not receiving any other medications associated with Sweet syndrome during treatment. Skin eruptions have been associated with molecular-targeted therapy, and our description of FLT3 inhibitor–associated neutrophilic dermatoses represents an additional agent-associated cutaneous complication of molecular-targeted therapy of AML.

Conclusions

FLT3-targeted therapy has entered phase 3 testing, and off-label use of drugs to treat FLT3-positive AML has become increasingly common. It is important for dermatologists to be aware of the potential for FLT3 inhibition to generate neutrophilic dermatoses during treatment response to this class of agents alone or as a manifestation of systemic differentiation syndrome.

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Article Information

Corresponding Author: Misha Rosenbach, MD, Department of Dermatology and Medicine, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St, Second Floor, Maloney Building, Philadelphia, PA 19104 (misha.rosenbach@uphs.upenn.edu).

Accepted for Publication: December 11, 2015.

Published Online: February 17, 2016. doi:10.1001/jamadermatol.2015.6121.

Author Contributions: Drs Varadarajan and Rosenbach had full access to all 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: Varadarajan, Rosenbach.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Varadarajan, Boni, Bagg.

Critical revision of the manuscript for important intellectual content: Varadarajan, Elder, Micheletti, Perl, Rosenbach.

Statistical analysis: Varadarajan.

Administrative, technical, or material support: Varadarajan, Boni, Bagg, Micheletti, Rosenbach.

Study supervision: Micheletti, Rosenbach.

Conflict of Interest Disclosures: Dr Perl has reported serving as a consultant and/or member of the scientific advisory board at Astellas, Daichi Sankyo, and Arog, companies that manufacture FLT3 inhibitors. No other disclosures were reported.

Funding/Support: This study was supported in part by grant 1K23CA141054 from the National Cancer Institute.

Role of the Funder/Sponsor: The funding source of the FL3 inhibitor clinical trials was sent the article before publication and approved submission. The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

References
1.
Pemmaraju  N, Kantarjian  H, Ravandi  F, Cortes  J.  FLT3 inhibitors in the treatment of acute myeloid leukemia: the start of an era?  Cancer. 2011;117(15):3293-3304.PubMedGoogle ScholarCrossref
2.
Cancer Genome Atlas Research Network.  Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.  N Engl J Med. 2013;368(22):2059-2074.PubMedGoogle ScholarCrossref
3.
Levis  MJ, Perl  AE, Dombret  H,  et al.  Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation.  Blood. 2012;120(21):673.Google Scholar
4.
Perl  A, Altman  J, Cortes  J,  et al. Results of a first in-human, Phase 1/2 trial of ASP2215, a selective, potent oral inhibitor of FLT3/AXL, in patients with relapsed or refractory acute myeloid leukaemia. Paper presented at the 20th Congress of the European Hematology Association; June 11, 2015; Vienna, Austria.
5.
Sexauer  A, Perl  A, Yang  X,  et al.  Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AML.  Blood. 2012;120(20):4205-4214.PubMedGoogle ScholarCrossref
6.
Fathi  AT, Le  L, Hasserjian  RP, Sadrzadeh  H, Levis  M, Chen  YB.  FLT3 inhibitor–induced neutrophilic dermatosis.  Blood. 2013;122(2):239-242.PubMedGoogle ScholarCrossref
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