Successful Treatment With Imatinib in a Patient With ...

3 downloads 0 Views 508KB Size Report
described here will have to be addressed. The hematologic benefit of imatinib therapy in HES with. FIP1L1-PDGFRA has been confirmed in numerous studies, ...
Published Ahead of Print on January 21, 2014 as 10.1200/JCO.2012.48.0665 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.48.0665

JOURNAL OF CLINICAL ONCOLOGY

Successful Treatment With Imatinib in a Patient With Chronic Eosinophilic Leukemia Not Otherwise Specified Introduction The classification of eosinophilic disorders was revised in the updated WHO classification and distinguishes myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1; chronic eosinophilic leukemia (CEL) not otherwise specified (NOS); lymphocyte-variant hypereosinophilia; and idiopathic hypereosinophilic syndrome (HES).1,2 CEL NOS is defined by the absence of the Philadelphia chromosome or a rearrangement involving PDGFRA/B and FGFR1, and the exclusion of other acute or chronic primary marrow neoplasms associated with eosinophilia. CEL NOS is histologically characterized by an increase in blasts in the bone marrow or peripheral blood and/or evidence for clonality in the eosinophilic lineage.1 The WHO classification proposal also has therapeutic implications because a high proportion of patients with PDGFR lesions respond effectively to tyrosine kinase inhibitors and in particular to imatinib, even though up to 20% of those who do not carry these alterations may respond to the same treatment. We describe here the case of patient with CEL NOS presenting with M541L c-KIT mutation who achieved a rapid hematologic remission with imatinib treatment. Case Report A 45-year-old man was referred to our hematologic department for severe persistent eosinophilia at blood-cell count. The patient smoked 40 cigarettes per day and had a history of acute hepatitis B virus and positivity for hepatitis C virus (HCV) antibodies, for which he underwent periodic follow-up without any therapy until serum HCV RNA was detectable. A 4-year history of persistent eosinophilia of 1.5 ⫻ 109/L was present. In December 2011, after returning from a 10-day holiday in Sri Lanka, he experienced fever (maximum temperature, 39°C), weakness, night sweats, shortness of breath with nonproductive cough, and weight loss of approximately 10 kg. At the end of February 2012, because of the persistence of the described symptoms and the beginning of unexplained right leg pain, the patient was admitted to the infectious diseases department. Laboratory results revealed leukocytosis (WBC count, 17 ⫻ 109/L; severe eosinophilia, 8.1 ⫻ 109/L). Blood cultures for bacteria and fungi and urine analysis were negative, as were HIV serologic tests. Stool examination showed the presence of Giardia duodenalis, and therefore, antiprotozoan treatment with metronidazole was started, with elimination of the parasitic infestation. HCV antibodies were positive, with HCV RNA undetectable viral load. Diagnostic workup for vasculitis, including antineutrophil cytoplasmic antibodies, anticardiolipin antibodies, anti-␤2 glycoprotein, was negative. Abdomen ultrasound scan was performed and showed liver enlargement without nodular lesions; spleen diameter was 12 cm. Total-body computed tomography (CT) Journal of Clinical Oncology, Vol 32, 2014

D I A G N O S I S

I N

O N C O L O G Y

scan was performed and showed no abscesses and/or lymphadenopathy. Positron emission tomography (PET) scan revealed no areas of abnormal glucose metabolism. Thrombosis in the popliteal vein of the right leg was diagnosed, and anticoagulation with low–molecular weight heparin was prescribed. In March 2012, the patient was referred to our hematologic center. Laboratory tests were as follows: hemoglobin, 8.9 g/dL; WBC count, 15.27 ⫻ 109/L (neutrophils, 52%; eosinophils, 15%; metamyelocytes, 15%); platelet count, 155 ⫻ 109/L; lactate dehydrogenase, 707 U/L; AST, 55 IU/L; ALT, 105 UI/L; ␥GT, 210 U/L; total bilirubin, 0.8 mg/dL; lipase, 31 U/L; amylase, 14 U/L; prothrombin time, 1.4; partial thromboplastin time, 0.83; D-dimer, 893 ng/mL; serum tryptase, 8 ng/mL; and immunoglobulin E level, 300 UI/mL. Abdomen ultrasound examination showed enlarged liver with nonhomogeneous parenchyma, dilation of the portal vein (15-mm diameter) without evidence of thrombosis, and enlarged spleen measuring 14 cm. Bone marrow biopsy and aspirate evaluation at diagnosis showed hypercellular marrow (95% to 100%), with hypoplastic erythropoiesis and diseryithropoietic findings, and hyperplastic granulopoiesis, with increase mature and immature eosinophils. Megakaryocytes were slightly increased, sometimes in loose clusters, and generally presented vescicular or hypolobulated nuclei (Fig 1). Less than 5% of CD34⫹ hematopoietic precursors were detectable. Mild interstitial and nodular lymphocytic infiltrations of approximately 5% to 10% were composed of small elements with mixed B and T phenotypes and some polyclonal plasma cells. A few round mast cells (⬍ 5%), tryptase positive CD2⫺ and CD25⫺, were identifiable. There was no T-cell receptor gene rearrangement. A diffuse and dense increase in reticulin fibers with extensive intersections and occasional focal bundles of collagen was evident, with Gomori’s silver impregnation (MF-2 according to WHO 2008 classification).

Fig 1.

© 2014 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on January 22, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.

Copyright 2014 by American Society of Clinical Oncology

1

Iurlo et al

Bone marrow aspirate flow cytometry showed CD117⫹ and CD34⫹ myeloid blast cells (0.2%), mature monocytes (4%), and hematogones (0.6%). Lymphocytes were 35%, represented by B (10%) and T lymphocytes (85%), with an inverted ratio of CD4 to CD8 (0.7). There was a CD3⫹ CD4⫹ CD8⫹ lymphoid population of approximately 6%. Peripheral blood showed CD4⫹ monocytes of 6%, T lymphocytes with normal ratio of CD4 to CD8 of 84%, and policlonal B lymphocytes of 16%. Cytogenetic analysis showed normal karyotype. The polymerase chain reaction was found negative for BCR-ABL, BCR-FGFR1, TEL-PDGFRB, and FIPL1-PDGFRA translocations and JAK2 mutation. WT1 quantitative analysis on peripheral blood showed 73 WT-1 copies and 104 ABL copies (peripheral blood range, 0 to 15). c-KIT analysis of exons 8, 9, 10, 11, 13, 14, and 17 showed M541L mutation on exon 10. According to WHO 2008 classification, a diagnosis of CEL NOS was made. Because of the persistent dyspnea, a new chest CT scan was performed and showed a pericardial effusion of approximately 3 cm, which was also confirmed on ultrasound examination. Pulmonary function tests resulted in a mixed disventilatory syndrome with an obstructive component partially reversible after 400 mcg of salbutamol administration. The patient was treated with high-dose oral steroids (prednisone 1 mg/kg daily) for 20 days, which resulted in improvement of fever without eosinophil count modification. Progressive worsening of patient clinical conditions was observed. Therefore, at the end of March 2012, a decision was made to start empirical treatment with imatinib 400 mg daily, which was progressively reduced to a maintenance dose of 100 mg daily. Eosinophil count normalized after 3 days of therapy, as did body temperature. After 2 months of therapy, the patient achieved a dramatic clinical improvement in weakness, night sweats, shortness of breath, and cough. The peripheral blood count normalized, with persistence of only an inverted formula (WBC, 6.48 ⫻ 109/L; neutrophils, 2.38 ⫻ 109/L; eosinophils, 0.31 ⫻ 109/L; lymphocytes, 3.17 ⫻ 109/L). Serum tryptase was unmodified at 8 ng/mL. Ultrasound examinations showed a complete resolution of pericardial effusion, with normal spleen diameters and reduction of liver enlargement. Pulmonary function tests were within normal limits. Bone marrow re-evaluation showed normocellular bone marrow, with only slight increase in the eosinophilic component (Fig 2). CD34⫹ cells were 1% to 2%. Mast cells (tryptase positive, CD2⫺, and CD25⫺) were approximately 5%, isolated and in rare clusters (⬍ 15 elements) without spindle-cell morphology. Bone marrow fibrosis was decreased (MF-0). Molecular re-evaluation of the presence of M541L c-KIT was negative after therapy. Discussion Hypereosinophilic syndromes are a rare heterogeneous group of hematologic diseases characterized by marked peripheral blood and tissue eosinophilia. Clinical presentation is also extremely heterogeneous, ranging from asymptomatic eosinophilia to lifethreatening organ failure (lung, heart, GI tract), caused by the release of eosinophil granule contents including major basic protein, eosinophilic cationic protein, and eosinophil-derived neurotoxin that directly damage endothelium.3,4 Because the crosstalk between eosinophils and mast cells is well known, inducing mast-cell activation by major basic protein 2

© 2014 by American Society of Clinical Oncology

Fig 2.

and stem-cell factor (or c-KIT ligand),5,6 the question arises of whether CEL NOS M541L c-KIT–associated mastocytic infiltration is clonally derived from the neoplastic clone. The persistence of mast cells in the follow-up bone marrow, without morphologic and immunophenotypic features of systemic mastocytosis, that resulted negative for the presence of M541L c-KIT, suggests that mast-cell differentiation is still cytokine dependent and could not be clonally derived. Although the heterozygosity of the M541L c-KIT allele (4894A/C) was estimated at approximately 20% in European whites, the functional effects of somatic M541L c-KIT described here will have to be addressed. The hematologic benefit of imatinib therapy in HES with FIP1L1-PDGFRA has been confirmed in numerous studies, but its role is still controversial in patients with CEL NOS or HES without a demonstrable FIP1L1-PDGFRA mutation.7 Hematologic responses in this group are more often partial and short lived compared with those occurring in patients with PDGFRA-associated disease and may reflect drug-related myelosuppression.8,9 Our patient was characterized by an extremely rapid eosinophil clearance (normalization of eosinophil count in a few days), with a complete response also at bone marrow evaluation and dramatic improvement of eosinophil-related symptoms. Currently, he is in hematologic remission and good clinical condition. Our analysis of the c-KIT gene identified a possible polymorphic somatic mutation, the pathogenetic implications of which were ruled out in different previous studies.9 Rare complete responses, as in the case described, may be explained by occult PDGFRA or PDGFRB rearrangements or other unknown pathogenetic targets as point mutations affecting these genes and support imatinib empiric treatment in these patient cases. The molecular characterization of this subset of patients responding to imatinib may contribute to an understanding of the pathophysiology of these rare disorders and suggest new therapeutic targets.

Alessandra Iurlo, Nicola Stefano Fracchiolla, Valeria Ferla, and Ramona Cassin Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda–Maggiore Policlinico Hospital Foundation, Milan, Italy JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on January 22, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.

Diagnosis in Oncology

Enrico Gottardi University of Turin, Turin, Italy

Alessandro Beghini University of Milan, Milan, Italy

Umberto Gianelli Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda–Maggiore Policlinico Hospital Foundation; and University of Milan, Milan, Italy

Orietta Spinelli Ospedali Riuniti di Bergamo, Bergamo, Italy

Agostino Cortelezzi Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda–Maggiore Policlinico Hospital Foundation; and University of Milan, Milan, Italy

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest. REFERENCES 1. Bain BJ, Gilliland DG, Horny HP, et al: Chronic eosinophilic leukaemia, not otherwise specified, in Swerdlow S, Harris NL, Stein H, et al (eds): WHO Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France, IARC Press, 2008, pp 51-53

2. Gotlib J: World Health Organization-defined eosinophilic disorders: 2011 update on diagnosis, risk stratification, and management. Am J Hematol 86:677688, 2011 3. Tefferi A, Gotlib J, Pardanani A: Hypereosinophilic syndrome and clonal eosinophilia: Point-of-care diagnostic algorithm and treatment update. Mayo Clin Proc 85:158-164, 2010 4. Wang LN, Pan Q, Fu JF, et al: FIP1L1-PDGFR␣ alone or with other genetic abnormalities reveals disease progression in chronic eosinophilic leukemia but good response to imatinib. Chin Med J (Engl) 121:867-873, 2008 5. Rothenberg ME, Hogan SP: The eosinophil. Annu Rev Immunol 24:147-174, 2006 6. Cairoli R, Ripamonti CB, Beghini A, et al: Total serum tryptase: A predictive marker for KIT mutation in acute myeloid leukemia. Leuk Res 33:1282-1284, 2009 7. Butterfield JH: Success of short-term, higher-dose imatinib mesylate to induce clinical response in FIP1L1-PDGFRalpha-negative hypereosinophilic syndrome. Leuk Res 33:1127-1129, 2009 8. Cools J, DeAngelo DJ, Gotlib J, et al: A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 348:1201-1214, 2003 9. Baccarani M, Cilloni D, Rondoni M, et al: The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome: Results of a multicenter prospective study. Haematologica 92:1173-1179, 2007

DOI: 10.1200/JCO.2012.48.0665; published online ahead of print at www.jco.org on January 21, 2014

■ ■ ■

www.jco.org

© 2014 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on January 22, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.

3