Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia

9 Haematology Department, University Hospital Trust and Cancer Sciences Unit, Cancer Research UK and National Institute for Health Research Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;

Alessandro Gozzetti

10 Hematology, Azienda Ospedaliera Universitaria Senese, Siena, Italy;

Anthony D. Ho

11 Department of Medicine V, University of Heidelberg, Heidelberg, Germany;

James B. Johnston

3 Section of Hematology/Oncology, University of Manitoba, Winnipeg, MB, Canada;

Jeffrey Jones

1 Division of Hematology, Department of Internal Medicine, The Ohio State University James Cancer Hospital, Columbus, OH;

Gunnar Juliusson

12 Department of Hematology, Skåne University Hospital and Stem Cell Center, Lund University, Lund, Sweden;

Eric Kraut

1 Division of Hematology, Department of Internal Medicine, The Ohio State University James Cancer Hospital, Columbus, OH;

Robert J. Kreitman

13 Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD;

Loree Larratt

14 Department of Medicine, University of Alberta, Edmonton, AB, Canada;

Francesco Lauria

10 Hematology, Azienda Ospedaliera Universitaria Senese, Siena, Italy;

Gerard Lozanski

15 Department of Pathology, The Ohio State University, Columbus, OH;

Emili Montserrat

16 Department of Hematology, Hospital Clinic, University of Barcelona, Barcelona, Spain;

Sameer A. Parikh

5 Division of Hematology, Mayo Clinic, Rochester, MN;

Jae H. Park

2 Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;

Aaron Polliack

17 Department of Hematology, Hadassah University Hospital and Hebrew University Medical School, Jerusalem, Israel;

Graeme R. Quest

18 Department of Laboratory Medicine and Pathology, University Health Network, Toronto, ON, Canada;

Kanti R. Rai

4 Department of Medicine, Hofstra North Shore-Long Island Jewish School of Medicine, Hofstra University, Hempstead, NY;

Farhad Ravandi

19 Section of Developmental Therapeutics, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX;

Tadeusz Robak

20 Department of Hematology, Medical University of Lodz, Lodz, Poland;

Alan Saven

21 Division of Hematology and Oncology, Scripps Clinic, La Jolla, CA;

John F. Seymour

22 Haematology Department, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia;

Tamar Tadmor

23 Hematology Unit, Bnai-Zion Medical Center, and the Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel;

Martin S. Tallman

2 Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;

Constantine Tam

22 Haematology Department, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia;

Enrico Tiacci

24 Institute of Hematology, Department of Medicine, University and Hospital of Perugia, Perugia, Italy;

Xavier Troussard

25 Department of Hematology, Centre Hospitalier Universitaire Côte de Nacre, Caen, France;

Clive S. Zent

26 James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY;

Thorsten Zenz

27 Department of Molecular Therapy in Hematology and Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany; and

Pier Luigi Zinzani

28 Institute of Hematology “Seràgnoli,” University of Bologna, Bologna, Italy

Brunangelo Falini

24 Institute of Hematology, Department of Medicine, University and Hospital of Perugia, Perugia, Italy;

1 Division of Hematology, Department of Internal Medicine, The Ohio State University James Cancer Hospital, Columbus, OH;

4 Department of Medicine, Hofstra North Shore-Long Island Jewish School of Medicine, Hofstra University, Hempstead, NY;

9 Haematology Department, University Hospital Trust and Cancer Sciences Unit, Cancer Research UK and National Institute for Health Research Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;

12 Department of Hematology, Skåne University Hospital and Stem Cell Center, Lund University, Lund, Sweden;

13 Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD;

17 Department of Hematology, Hadassah University Hospital and Hebrew University Medical School, Jerusalem, Israel;

19 Section of Developmental Therapeutics, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX;

22 Haematology Department, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia;

23 Hematology Unit, Bnai-Zion Medical Center, and the Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel;

24 Institute of Hematology, Department of Medicine, University and Hospital of Perugia, Perugia, Italy;

27 Department of Molecular Therapy in Hematology and Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany; and

Abstract

Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.

Background

Hairy cell leukemia (HCL) is an uncommon chronic B-cell leukemia initially described by 2 independent investigators who established this as a distinct clinical entity. 1,2 Although the initial term describing this disease was leukemic reticuloendotheliosis, the cell of origin was established to be a mature B cell. 3 In 2008, the World Health Organization) determined that the classic form of hairy cell leukemia (HCLc) should be recognized as separate from the rarer variant of this disease called hairy cell leukemia variant (HCLv). 4 The observation that a specific mutation, BRAF V600E , is present in the overwhelming majority of patients with HCLc and absent in HCLv validates the clinical observation that HCLv follows a different clinical course and response to therapy. 5,6 Recently, Chung et al 7 showed that hematopoietic stem cells from the bone marrow of patients with HCLc expressing the BRAF V600E mutation have self-renewal potential. The BRAF V600E mutation was also shown to play a key role in shaping the specific molecular signature, morphology, and antiapoptotic behavior of HCL. 8 Molecular and genomic studies identify prognostic factors in HCL that are associated with different responses to therapy. 9 -13 The consistent application of these respective prognostic parameters may have an impact on the optimal management of patients.

The introduction of the purine nucleoside analogs (cladribine and pentostatin) either alone or in combination with an anti-CD20 monoclonal antibody secured durable complete responses. 14 -21 Nevertheless, patients relapse and require additional therapy. Substantial variability has been introduced into how these agents are administered. 22 -24 Mature data regarding long-term follow-up has shown the effectiveness of the purine analogs delivered either by continuous infusion or subcutaneous injection (eg, cladribine) or by intravenous administration (pentostatin). 22,25 -28 Because more patients are treated with alternative regimens, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease (MRD). The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials. 29 In an effort to clarify the approach to diagnosis, the criteria for initiating therapy, and the selection of therapy followed by an assessment of response, the Hairy Cell Leukemia Foundation convened an international conference to establish consensus on managing patients with HCL. In addition, recommendations were considered for how to approach the patient with relapse who requires re-treatment. The unresolved but important question on how patients with active infection should best be managed and recommendations for incorporating prophylaxis for infection were discussed. Hopefully, the adoption of consensus guidelines will enable international experts to continue making progress toward improving the quality of life of patients despite the diagnosis of leukemia.

Establishing the diagnosis

Patients often present with symptoms of fatigue and infection. 1,2,30,31 Although patients in the past often presented with an enlarged spleen (approximately 90%), this finding appears to be much less frequent as a result of earlier detection of disease. More commonly, patients present because of incidental findings of pancytopenia. 30,31 The initial evaluation should include careful review of the peripheral blood smear with a differential count; monocytopenia is a relatively sensitive and specific manifestation of HCLc. Leukemic cells are often rare. Hairy cells are medium in size with moderately abundant pale blue cytoplasm, reniform nuclei, open chromatin, absent nucleoli, and a characteristic serrated cytoplasmic border ( Figure 1 ). In Table 1 , the recommended initial work-up is presented for HCL and other clinical entities that may mimic this disease (eg, HCLv, splenic marginal zone lymphoma, and splenic diffuse red pulp small B-cell lymphoma).

Histologic image of a hairy cell. Wright-Giemsa stained smear of peripheral blood. This image was obtained by using a UPlanFL 100 Olympus objective oil immersion lens. The image was obtained by using an MTI 3 CCD camera (DAGE-MTI Inc.) with PAX-it 2.0 acquisition software (MIS).