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Recommendations of the SFH (French Society of Haematology) for the diagnosis, treatment and follow-up of hairy cell leukaemia

Recommendations of the SFH (French Society of Haematology) for the diagnosis, treatment and... Ann Hematol (2014) 93:1977–1983 DOI 10.1007/s00277-014-2140-y ORIGINAL ARTICLE Recommendations of the SFH (French Society of Haematology) for the diagnosis, treatment and follow-up of hairy cell leukaemia Edouard Cornet & Alain Delmer & Pierre Feugier & Francine Garnache-Ottou & David Ghez & Véronique Leblond & Vincent Levy & Frédéric Maloisel & Daniel Re & Jean-Marc Zini & Xavier Troussard Received: 7 May 2014 /Accepted: 16 June 2014 /Published online: 5 July 2014 The Author(s) 2014. This article is published with open access at Springerlink.com Abstract Hairy cell leukaemia (HCL) is a rare haematologi- belonging to a number of French hospitals. This group met in cal malignancy, with approximately 175 new incident cases in November 2013 to examine the criteria for managing patients France. Diagnosis is based on a careful examination of the with HCL. The ideas and proposals of the group are based on blood smear and immunophenotyping of the tumour cells, a critical analysis of the recommendations already published with a panel of four markers being used specifically to screen in the literature and on an analysis of the practices of clinical for hairy cells (CD11c, CD25, CD103 and CD123). In 2011, haematology departments with experience in managing these the V600E mutation of the BRAF gene in exon 15 was patients. The first-line treatment uses purine analogues: identified in HCL; being present in HCL, it is absent in the cladribine or pentostatin. The role of BRAF inhibitors, variant form of HCL (HCL-v) and in splenic red pulp lym- whether or not combined with MEK inhibitors, is phoma (SRPL), two entities related to HCL. The management discussed. The panel of French experts proposed recom- of patients with HCL has changed in recent years. A poorer mendationstomanagepatientswithHCL, which canbe response to purine nucleoside analogues (PNAs) is observed used in a daily practice. in patients with more marked leukocytosis, bulky splenomeg- aly, an unmutated immunoglobulin variable heavy chain . . (IgVH)gene profile, use of VH4–34 or with TP53 mutations. Keywords Hairy cell leukaemia Recommendations We present the recommendations of a group of 11 experts Diagnosis Treatment E. Cornet X. Troussard (*) V. Levy Haematology Laboratory, Caen University Hospital, 14033 Caen Haematology Oncology Thorax Division, Hôpital Avicenne, Cedex, France 93003 Bobigny Cedex, France e-mail: troussard-x@chu-caen.fr F. Maloisel A. Delmer Sainte Anne Clinic, 67085 Strasbourg Cedex, France Department of Clinical Haematology, Reims University Hospital, 51092 Reims Cedex, France D. Re P. Feugier Antibes Hospital, 06100 Nice Cedex, France Haematology Division, Nancy University Hospital, 54035 Nancy Cedex, France D. Re F. Garnache-Ottou Antoine Lacassagne Centre (Nice), 06100 Nice Cedex, France EFS, BFC, 25020 Besançon Cedex, France D. Ghez J.<M. Zini Gustave Roussy, 94805 Villejuif Cedex, France Saint Louis Hospital, 75010 Paris Cedex, France V. Leblond Department of Clinical Haematology, Pitié Salpêtrière Hospital, X. Troussard 75651 Paris Cedex, France Haematology Laboratory, CHU de Caen, 14000 Caen, France 1978 Ann Hematol (2014) 93:1977–1983 Background In all cases, the diagnosis is based on a careful examination of the blood smear and immunophenotyping of the tumour The epidemiological data relating to hairy cell leukaemia cells. (HCL) are limited. HCL is a rare haematological malignancy, representing 2 % of all leukaemia [1]. Between 1992 and Identification of hairy cells in the blood smear 2000, a review of 12 American databases covering 14 % of the American population revealed a higher frequency of HCL Hairy cells—large cells with abundant, poorly demarcated, among white Americans than among African Americans or grey to weakly and irregularly basophilic cytoplasm—display Asians [2]. The data from the lower Normandy Regional fine cytoplasmic projections distributed around the entire Register of Haematological Malignancies indicate an inci- circumference of the cell. “Granular/lamellar” cytoplasmic dence standardized to the world population of 0.29±0.08 per inclusions with the appearance of slightly basophilic rods with 100,000. The incidence is higher in men (0.50±0.15) than in a clear central area are detected occasionally. The nucleus-to- women (0.12±0.008) [3]. These data, extrapolated to France, cytoplasm ratio is low, and the nucleus is often in an eccentric suggest approximately 175 incident cases of HCL per year. position. Oval or round, it can sometimes be kidney-shaped. The median age of patients at diagnosis is 52 (24–81). The The nuclear chromatin has a dispersed appearance and never SEER (Surveillance, Epidemiology and End Results Program; coarse, and the nucleolus, which is not readily seen, is small http://seer.cancer.gov) study conducted in 3,776 patients and often solitary. Sometimes difficult to identify in a poor shows an improvement in survival over the calendar periods quality smear, the cells are found consistently in the blood analysed (before 1984, 1984–1990, 1991–1999 and 2000– smear, even if only in small numbers. 2008) and a reduction in the risk of mortality of 6.5 % per Monocytopenia is almost always present. It may be erro- year. The survival rate for HCL is lower among African neously absent from the results yielded by automated Americans [4]. haematology analysers, which regularly identify hairy cells The causes of HCL remain unknown. The existence of as monocytes. There is no lymphocytosis. Neutropenia, anae- familial forms suggests a genetic predisposition in some cases mia that is often mildly macrocytic and thrombocytopenia of [1]. The role of certain environmental factors remains unclear; varying severity often complete the constellation of laboratory a risk associated with forage growing or exposure to organo- findings. phosphate insecticides has been identified, as has a tobacco- associated protective effect [5]. In 2011, mutations were iden- tified in five genes (BRAF, CSMD3, SLC5A1, CNTN6 and Immunophenotype OR8J) by means of whole-exome high-throughput sequenc- ing performed on the (>90 %) CD19 tumour cells from a Immunophenotyping can be performed on blood or bone patient with HCL and on the (>98 %) CD19 mononuclear marrow. Hairy cells must be looked for within a large cell cells from the same patient at the time of remission [6]. The gate (in the vicinity of the monocyte gate). V600E mutation of the BRAF gene in exon 15 was confirmed It comprises an analysis of the B cell lineage markers by means of direct sequencing in 47 other patients with HCL. (CD19, CD20) combined with a panel of markers used spe- However, it was absent in 195 patients with another chronic B cifically to screen for hairy cells (CD11c, CD25, CD103, cell lymphoproliferative disorder, including patients with mar- CD123) and screening for an immunoglobulin light chain ginal zone lymphoma. isotype restriction. HCL may be associated with other haematological malig- The four markers CD11c, CD25, CD103 and CD123 de- nancies, particularly multiple myeloma (MM), large granular fine the HCL score [8], which distinguishes HCL from other B lymphocytic leukaemia (LGL) or chronic myeloid leukaemia cell haematological disorders associated with hairy cells, in- (CML) [7]. cluding the variant form of HCL (HCL-v), splenic marginal zone lymphoma (SMZL) and splenic red pulp lymphoma (SRPL). One point is given to each marker when it is expressed, and no point is given when it is not expressed. A Diagnosis score of 3 or 4 is observed in 98 % of cases of HCL, unlike with other B cell haematological disorders associated with The circumstances under which the disease is discovered are hairy cells, where the score is usually 0 or 1. It is not compul- related to the consequences of bone marrow suppression, sory to calculate this score, the co-expression of the markers including severe or recurrent infections, to the detection of CD11c, CD25 and CD103 representing a sufficient basis on splenomegaly, whether symptomatic or not, or to the often which to diagnose HCL. If a negative result is obtained for one fortuitous identification of hairy cells during a routine blood of these three markers, there is a need to assess the expression of CD123 and to calculate this score. count. Ann Hematol (2014) 93:1977–1983 1979 Although there is no need to calculate it for the diagnosis of Differential diagnosis HCL, the Royal Marsden Hospital (RMH) score [9]used in chronic lymphocytic leukaemia (CLL) is usually 0 or 1. The variant form of HCL and SRPL constitutes forms which are difficult to diagnose with areas of overlap with HCL [12]. Bone marrow examination Variant form of HCL This is not obligatory, except in clinical trials. Where diagnosis proves difficult or immunophenotyping is Despite being described as long ago as 1980 [13], the variant inconclusive and the number of hairy cells present is small, a form of HCL (HCL-v) is a rare entity (10 % of all cases of bone marrow biopsy combined with bone marrow aspiration is HCL). The terminology is ambiguous, because it is a disorder desirable. Hairy cells, cells which are easily recognizable by their distinct from HCL. It affects men, with a median age of oval or kidney-shaped nuclei, their chromatin pattern, the clear 71 years (48–92 years) [14,15]. Monocytopenia is absent, “halo” which separates the nuclei and the abundant cytoplasm and leukocytosis is >10×10 /L in more than 90 % of cases. which is difficult to see, have a typical “fried egg” appearance. Examination of the blood smear shows a proliferation of hairy Immunohistochemistry (IHC) is sometimes useful for de- cells (20–95 % of the lymphoid cells) of medium to large size tecting hairy cells in limited numbers—expression of the with a large and clearly visible nucleolus and condensed isoenzyme 5 of tartrate acid-resistant phosphatase (TRAP) in chromatin. There is infiltration of the splenic red pulp. The the form of non-specific but characteristic granular cytoplasm HCL score is low (0, 1 or 2) with a strong expression of positivity, expression of CD20 and CD72 and the mutated CD11c (87 %) and CD103 (60 %) contrasting with a weak, BRAF protein [10]. rare expression of CD123 (7 %) or CD25 (6 %) [15,16]. The BRAF V600E mutation is absent. Cytogenetic and molecular analyses Cytogenetic studies and BRAF V600E mutation testing [6,11] Splenic red pulp lymphoma or SRPL are not necessary for diagnosis. BRAF V600E mutation testing may be useful in cases of diagnostic uncertainty and in cases SRPL is rare [17] and was described recently. It affects men where therapeutic management is complex. (sex ratio, 1.64) with a median age of 77 years (46–91). In three quarters of cases, lymphocytosis is present and exami- Other investigations at diagnosis nation of the blood smear shows the presence of a proliferation of hairy cells (median, 60 %; 26–91 % of the lymphoid cells) Clinical evaluation must include the following: of small to medium size with, in the majority of cells, a small or invisible nucleolus. The cellular phenotype is very hetero- – A patient history, looking for any familial history of geneous, quite close to HCL-v, with a strong expression of haematological malignancy or autoimmune disorders; CD11c (97 %), a variable expression of CD103 (38 %) and – Identification of any systemic symptoms; little or no expression of CD123 (16 %) and CD25 (3 %). The – Checking for signs of disease, especially checking for blood karyotype may show anomalies such as 7q deletion. splenomegaly. The use of imaging can be helpful for this. The immunoglobulin variable heavy chain (IgVH)gene pro- Ultrasonography of the spleen can be used to measure the file is mutated in 80 % of cases, with over-represented use of size of the spleen and to identify abdominal lymphade- VH3–26 and VH4–34. The BRAF V600E mutation is absent nopathy, which is uncommon. in SRPL. Biological tests include the following: – A complete blood count with differential including a reticulocyte count; Required pretreatment evaluation – Serum protein electrophoresis to look for a monoclonal component; Assessment of prognostic factors – Haemolysis screen in the presence of suspicion. Unless there is a therapeutic indication, there is no justification The following is desirable: for carrying out any additional investigations for the assess- ment of prognostic factors. No prognostic factor will modify – Preservation of tumour material in blood and/or bone the choice of first-line treatment, which is based on purine marrow before any treatment. nucleoside analogues (PNAs): cladribine or pentostatin. 1980 Ann Hematol (2014) 93:1977–1983 Studies in patients treated with cladribine have resulted in Treatment the identification of factors, which may reduce the following Indications for treatment responses to treatment: Criteria for initiating treatment may vary depending on wheth- – Leukocytosis >10×10 /L [18] – Bulky spleen extending >10 cm below costal margin [18] er or not the patient is treated in a clinical trial. In general practice, treatment is indicated in the presence of at least one – Unmutated IgVH gene profile ≥98 % [18] – Use of the VH4–34 repertoire [19] of the signs of active disease as follows: – Mutation of the TP53 gene [18]. 1. Symptomatic splenomegaly Other factors reduce event-free survival (EFS) [18]as 2. Cytopenia (involving at least one cell type) follows: (a) Haemoglobin <10 g/dL (b) Platelets <100×10 /L – Bulky spleen extending >10 cm below costal margin – Elevated levels of circulating hairy cells >10×10 /L (c) Neutrophils <1×10 /L 3. Recurrent or severe infections – Unmutated IgVH profile. In the absence of treatment, clinical monitoring and mon- TP53 mutation testing and analysis of the IgVH gene repertoire to test for VH4–34 positivity must be performed itoring of the blood count are necessary every 3 months for the first year and then every 6 months. in the event of a relapse, before the second line of treatment, on previously frozen material or fresh material if possible. Treatment strategy Pretreatment assessment Inclusion in a prospective study protocol is recommended. In Parameters considered necessary for a complete pretreatment general practice, the recommendations are as follows. evaluation may differ depending on whether or not the patient is treated in a clinical protocol. First-line treatment The following are essential pretreatment tests (clinical trials and general practice): The first-line treatment is based on PNAs [20–22]: cladribine or pentostatin. The different dosing regimens for the two medicinal products are listed in Table 1. – Physical examination including the determination of the performance status as defined by the Eastern Cooperative There are no data in the literature proving the superiority of Oncology Group (ECOG) and the identification of co- one drug over the other. The choice between pentostatin and morbidities and potential sites of infection. cladribine is based essentially on the presence or absence of – Serum chemistry including creatinine with calculation of renal impairment, the severity of the cytopenias and the dosing creatinine clearance (Modification of Diet in Renal Dis- regimens of the products. Cladribine may be used intrave- ease (MDRD) Study), haemolysis screen (direct antiglob- nously (IV) or subcutaneously (SC), unlike pentostatin, which ulin test, haptoglobin, unconjugated bilirubin and lactic is used only via the IV route. The SC form offers ease of dehydrogenase) and liver function tests (transaminases) administration and the option of treatment on an outpatient basis, unlike cladribine IV. with hepatitis B and C serology (risk of reactivation after immunosuppressive therapy). In the presence of renal impairment (plasma creatinine clearance (MDRD) <60 mL/min), pentostatin is contraindi- – Preservation of cells and serum in a tumour bank is recommended. cated owing to limited experience, unlike cladribine. – Chest radiograph and abdominal and pelvic imaging. Special cases The following are additional pretreatment tests that may be performed in clinical trials: In cases of severe neutropenia (neutrophil count <0.2×10 /L) and/or uncontrolled active infection, the treatment of choice is – Blood and bone marrow karyotypes analysis. interferon via the SC route at a dose of 3 million units×3 per – BRAF V600E mutation testing. week followed by a purine analogue once the neutropenia has – Mutational status of IgVH gene and analysis of the VH been corrected. Another option, although not validated in this gene usage. indication, is the use of rituximab on its own at a dose of – Mutational status of TP53 gene. 375 mg/m IV for 4 weeks in the place of interferon. Ann Hematol (2014) 93:1977–1983 1981 Table 1 Different dosing regimens In cases of early relapse (<24 months), the diagnosis of HCL must be confirmed and BRAF V600E mutation testing Dosing regimen for cladribine (2-chlorodeoxyadenosine (2-CDA)) must be performed. Authorized dosages 0.14 mg/kg/day SC for 5 days 1. If the diagnosis of HCL is confirmed, the management 0.1 mg/kg/day as a continuous IV infusion for 7 days approach will depend on the presence or absence of a Other dosages (off-label) TP53 gene mutation and VH4–34 use. 0.14 mg/kg/day as an IV infusion over 2 h for 5 days 0.14 mg/kg/day IV once weekly for 6 weeks (a) In the absence of the TP53 gene mutation, with a VH repertoire other than VH4–34, the use of a PNA 0.14 mg/kg/day SC once weekly for 5 weeks combined with rituximab is recommended. Thedosagemust berepeated inthe absence ofCRat 6 months (b) In cases of TP53 gene mutation [25] and/or use of Dosing regimen for pentostatin in HCL (2′-deoxycoformycin (2′-DCF)) VH4–34, the different treatment options are as follows: 4 mg/m every 2 weeks until a maximal response is achieved, plus one or two additional injections Determine the creatinine clearance before each administration and – Immunotoxins, but they are not available in France avoid the medicinal product in the presence of clearance <60 mL/ [26,27]. min – BRAF inhibitors either alone or in combination with Dosing regimen for rituximab (4–8 doses in total) MEK inhibitors. No treatment regimen is defined at pres- 375 mg/m IVonce weekly administered simultaneously or ent [28–31]. The use of these treatments must take into sequentially with the purine analogue in patients without CR after a account the toxicity of these drugs, including their cuta- single treatment with pentostatin or cladribine neous effects [30,32,33]. Interferon alpha (IFN-α) 6 – Bendamustine and rituximab in combination [34]. 3×10 U SC daily until a maximal response is achieved and continuation at the same dose three times weekly. In very cytopenic – If access to innovative compounds is impossible, a com- patients, start on a dose of 3×10 U 3 times weekly bination of treatment with PNA and rituximab is Splenectomy recommended. Indicated in cases of bulky splenomegaly (>10 cm below the costal 2. If the diagnosis of HCL is not confirmed and in the margin) and in cases of moderate bone marrow involvement, after absence of a BRAF V600E mutation, an analysis of the immunization programme IgVH repertoire to test for VH4–34 use must be per- formed. Treatment must be considered on a case-by-case basis. In cases of active haemolytic anaemia, consideration might be given to rituximab. Subsequent relapses Some options used before the era of In cases of pregnancy, the only treatment that can be used is PNAs should not be ruled out, including splenectomy and interferon via the SC route at a dose of 3 million units×3 per interferon. week. In cases of two co-existing haematological disorders or a Prevention of infectious complications concomitant haematological disorder, the management ap- proach should be discussed at a multidisciplinary meeting. The prevention of infectious complications occurring during the course of HCL treatment or in the post-treatment period is Relapses of prime importance. In the prevention of Pneumocystis jiroveci-induced in- Only symptomatic relapses require treatment. fections with Bactrim® until recovery of T cell numbers to CD4>200/mm , there is an increased risk of allergic skin First relapse In cases of late relapse (>60 months), PNAs may reactions during concomitant use of Bactrim® with purine be used again. No recommendations exist regarding whether analogues. This risk can be reduced by starting Bactrim® or not the PNAs should be changed. 1 week after the purine analogue. In cases of allergy to Bactrim® or cytopenias potentially linked to Bactrim®, In cases of intermediate relapse (24–60 months), the Pentacarinat® or atovaquone (Wellvone®) aerosols may be second-line treatment also relies on PNAs, whether or not a used. different PNA is used and whether or not it is combined with Prevention of zoster infections with aciclovir or rituximab, administered concomitantly or sequentially (non- valaciclovir should also be started 1 week after PNAs. The validated treatment regimens) [23,24]. optimal duration of prophylaxis has not been determined. 1982 Ann Hematol (2014) 93:1977–1983 Open Access This article is distributed under the terms of the Creative Growth factors should be considered on a case-by-case Commons Attribution License which permits any use, distribution, and basis. reproduction in any medium, provided the original author(s) and the No data in the literature provide a basis for either source are credited. recommending or not recommending the irradiation of labile blood products after treatment with purine analogues. References 1. Bernstein L, Newton P, Ross RK (1990) Epidemiology of hairy cell Response criteria and evaluation leukemia in Los Angeles County. Cancer Res 50(12):3605–3609 2. Morton L, Wang S, Devesa S, Hartge P, Weisenburger D, Linet M The following definitive response should be assessed: (2006) Lymphoma incidence patterns by who subtype in the United States, 1992–2001. 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Ravandi F, Jorgensen JL, O’Brien SM, Verstovsek S, Ca K, Molecular insight into the biology and clinical course of hairy cell Faderl S, Giles FJ, Ferrajoli A, Wierda WG, Odinga S, Huang leukemia utilizing immunoglobulin gene analysis. Leuk Lymphoma X, Thomas DA, Freireich EJ, Jones D, Keating MJ, Kantarjian 52(1):15–23. doi:10.3109/10428194.2010.530362 HM (2006) Eradication of minimal residual disease in hairy cell 26. Kreitman RJ, Tallman MS, Robak T, Coutre S, Wilson WH, Stetler- leukemia. Blood 107(12):4658–4662. doi:10.1182/Blood-2005- Stevenson M, Fitzgerald DJ, Lechleider R, Pastan I (2012) Phase I 11-4590 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Hematology Pubmed Central

Recommendations of the SFH (French Society of Haematology) for the diagnosis, treatment and follow-up of hairy cell leukaemia

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Abstract

Ann Hematol (2014) 93:1977–1983 DOI 10.1007/s00277-014-2140-y ORIGINAL ARTICLE Recommendations of the SFH (French Society of Haematology) for the diagnosis, treatment and follow-up of hairy cell leukaemia Edouard Cornet & Alain Delmer & Pierre Feugier & Francine Garnache-Ottou & David Ghez & Véronique Leblond & Vincent Levy & Frédéric Maloisel & Daniel Re & Jean-Marc Zini & Xavier Troussard Received: 7 May 2014 /Accepted: 16 June 2014 /Published online: 5 July 2014 The Author(s) 2014. This article is published with open access at Springerlink.com Abstract Hairy cell leukaemia (HCL) is a rare haematologi- belonging to a number of French hospitals. This group met in cal malignancy, with approximately 175 new incident cases in November 2013 to examine the criteria for managing patients France. Diagnosis is based on a careful examination of the with HCL. The ideas and proposals of the group are based on blood smear and immunophenotyping of the tumour cells, a critical analysis of the recommendations already published with a panel of four markers being used specifically to screen in the literature and on an analysis of the practices of clinical for hairy cells (CD11c, CD25, CD103 and CD123). In 2011, haematology departments with experience in managing these the V600E mutation of the BRAF gene in exon 15 was patients. The first-line treatment uses purine analogues: identified in HCL; being present in HCL, it is absent in the cladribine or pentostatin. The role of BRAF inhibitors, variant form of HCL (HCL-v) and in splenic red pulp lym- whether or not combined with MEK inhibitors, is phoma (SRPL), two entities related to HCL. The management discussed. The panel of French experts proposed recom- of patients with HCL has changed in recent years. A poorer mendationstomanagepatientswithHCL, which canbe response to purine nucleoside analogues (PNAs) is observed used in a daily practice. in patients with more marked leukocytosis, bulky splenomeg- aly, an unmutated immunoglobulin variable heavy chain . . (IgVH)gene profile, use of VH4–34 or with TP53 mutations. Keywords Hairy cell leukaemia Recommendations We present the recommendations of a group of 11 experts Diagnosis Treatment E. Cornet X. Troussard (*) V. Levy Haematology Laboratory, Caen University Hospital, 14033 Caen Haematology Oncology Thorax Division, Hôpital Avicenne, Cedex, France 93003 Bobigny Cedex, France e-mail: troussard-x@chu-caen.fr F. Maloisel A. Delmer Sainte Anne Clinic, 67085 Strasbourg Cedex, France Department of Clinical Haematology, Reims University Hospital, 51092 Reims Cedex, France D. Re P. Feugier Antibes Hospital, 06100 Nice Cedex, France Haematology Division, Nancy University Hospital, 54035 Nancy Cedex, France D. Re F. Garnache-Ottou Antoine Lacassagne Centre (Nice), 06100 Nice Cedex, France EFS, BFC, 25020 Besançon Cedex, France D. Ghez J.<M. Zini Gustave Roussy, 94805 Villejuif Cedex, France Saint Louis Hospital, 75010 Paris Cedex, France V. Leblond Department of Clinical Haematology, Pitié Salpêtrière Hospital, X. Troussard 75651 Paris Cedex, France Haematology Laboratory, CHU de Caen, 14000 Caen, France 1978 Ann Hematol (2014) 93:1977–1983 Background In all cases, the diagnosis is based on a careful examination of the blood smear and immunophenotyping of the tumour The epidemiological data relating to hairy cell leukaemia cells. (HCL) are limited. HCL is a rare haematological malignancy, representing 2 % of all leukaemia [1]. Between 1992 and Identification of hairy cells in the blood smear 2000, a review of 12 American databases covering 14 % of the American population revealed a higher frequency of HCL Hairy cells—large cells with abundant, poorly demarcated, among white Americans than among African Americans or grey to weakly and irregularly basophilic cytoplasm—display Asians [2]. The data from the lower Normandy Regional fine cytoplasmic projections distributed around the entire Register of Haematological Malignancies indicate an inci- circumference of the cell. “Granular/lamellar” cytoplasmic dence standardized to the world population of 0.29±0.08 per inclusions with the appearance of slightly basophilic rods with 100,000. The incidence is higher in men (0.50±0.15) than in a clear central area are detected occasionally. The nucleus-to- women (0.12±0.008) [3]. These data, extrapolated to France, cytoplasm ratio is low, and the nucleus is often in an eccentric suggest approximately 175 incident cases of HCL per year. position. Oval or round, it can sometimes be kidney-shaped. The median age of patients at diagnosis is 52 (24–81). The The nuclear chromatin has a dispersed appearance and never SEER (Surveillance, Epidemiology and End Results Program; coarse, and the nucleolus, which is not readily seen, is small http://seer.cancer.gov) study conducted in 3,776 patients and often solitary. Sometimes difficult to identify in a poor shows an improvement in survival over the calendar periods quality smear, the cells are found consistently in the blood analysed (before 1984, 1984–1990, 1991–1999 and 2000– smear, even if only in small numbers. 2008) and a reduction in the risk of mortality of 6.5 % per Monocytopenia is almost always present. It may be erro- year. The survival rate for HCL is lower among African neously absent from the results yielded by automated Americans [4]. haematology analysers, which regularly identify hairy cells The causes of HCL remain unknown. The existence of as monocytes. There is no lymphocytosis. Neutropenia, anae- familial forms suggests a genetic predisposition in some cases mia that is often mildly macrocytic and thrombocytopenia of [1]. The role of certain environmental factors remains unclear; varying severity often complete the constellation of laboratory a risk associated with forage growing or exposure to organo- findings. phosphate insecticides has been identified, as has a tobacco- associated protective effect [5]. In 2011, mutations were iden- tified in five genes (BRAF, CSMD3, SLC5A1, CNTN6 and Immunophenotype OR8J) by means of whole-exome high-throughput sequenc- ing performed on the (>90 %) CD19 tumour cells from a Immunophenotyping can be performed on blood or bone patient with HCL and on the (>98 %) CD19 mononuclear marrow. Hairy cells must be looked for within a large cell cells from the same patient at the time of remission [6]. The gate (in the vicinity of the monocyte gate). V600E mutation of the BRAF gene in exon 15 was confirmed It comprises an analysis of the B cell lineage markers by means of direct sequencing in 47 other patients with HCL. (CD19, CD20) combined with a panel of markers used spe- However, it was absent in 195 patients with another chronic B cifically to screen for hairy cells (CD11c, CD25, CD103, cell lymphoproliferative disorder, including patients with mar- CD123) and screening for an immunoglobulin light chain ginal zone lymphoma. isotype restriction. HCL may be associated with other haematological malig- The four markers CD11c, CD25, CD103 and CD123 de- nancies, particularly multiple myeloma (MM), large granular fine the HCL score [8], which distinguishes HCL from other B lymphocytic leukaemia (LGL) or chronic myeloid leukaemia cell haematological disorders associated with hairy cells, in- (CML) [7]. cluding the variant form of HCL (HCL-v), splenic marginal zone lymphoma (SMZL) and splenic red pulp lymphoma (SRPL). One point is given to each marker when it is expressed, and no point is given when it is not expressed. A Diagnosis score of 3 or 4 is observed in 98 % of cases of HCL, unlike with other B cell haematological disorders associated with The circumstances under which the disease is discovered are hairy cells, where the score is usually 0 or 1. It is not compul- related to the consequences of bone marrow suppression, sory to calculate this score, the co-expression of the markers including severe or recurrent infections, to the detection of CD11c, CD25 and CD103 representing a sufficient basis on splenomegaly, whether symptomatic or not, or to the often which to diagnose HCL. If a negative result is obtained for one fortuitous identification of hairy cells during a routine blood of these three markers, there is a need to assess the expression of CD123 and to calculate this score. count. Ann Hematol (2014) 93:1977–1983 1979 Although there is no need to calculate it for the diagnosis of Differential diagnosis HCL, the Royal Marsden Hospital (RMH) score [9]used in chronic lymphocytic leukaemia (CLL) is usually 0 or 1. The variant form of HCL and SRPL constitutes forms which are difficult to diagnose with areas of overlap with HCL [12]. Bone marrow examination Variant form of HCL This is not obligatory, except in clinical trials. Where diagnosis proves difficult or immunophenotyping is Despite being described as long ago as 1980 [13], the variant inconclusive and the number of hairy cells present is small, a form of HCL (HCL-v) is a rare entity (10 % of all cases of bone marrow biopsy combined with bone marrow aspiration is HCL). The terminology is ambiguous, because it is a disorder desirable. Hairy cells, cells which are easily recognizable by their distinct from HCL. It affects men, with a median age of oval or kidney-shaped nuclei, their chromatin pattern, the clear 71 years (48–92 years) [14,15]. Monocytopenia is absent, “halo” which separates the nuclei and the abundant cytoplasm and leukocytosis is >10×10 /L in more than 90 % of cases. which is difficult to see, have a typical “fried egg” appearance. Examination of the blood smear shows a proliferation of hairy Immunohistochemistry (IHC) is sometimes useful for de- cells (20–95 % of the lymphoid cells) of medium to large size tecting hairy cells in limited numbers—expression of the with a large and clearly visible nucleolus and condensed isoenzyme 5 of tartrate acid-resistant phosphatase (TRAP) in chromatin. There is infiltration of the splenic red pulp. The the form of non-specific but characteristic granular cytoplasm HCL score is low (0, 1 or 2) with a strong expression of positivity, expression of CD20 and CD72 and the mutated CD11c (87 %) and CD103 (60 %) contrasting with a weak, BRAF protein [10]. rare expression of CD123 (7 %) or CD25 (6 %) [15,16]. The BRAF V600E mutation is absent. Cytogenetic and molecular analyses Cytogenetic studies and BRAF V600E mutation testing [6,11] Splenic red pulp lymphoma or SRPL are not necessary for diagnosis. BRAF V600E mutation testing may be useful in cases of diagnostic uncertainty and in cases SRPL is rare [17] and was described recently. It affects men where therapeutic management is complex. (sex ratio, 1.64) with a median age of 77 years (46–91). In three quarters of cases, lymphocytosis is present and exami- Other investigations at diagnosis nation of the blood smear shows the presence of a proliferation of hairy cells (median, 60 %; 26–91 % of the lymphoid cells) Clinical evaluation must include the following: of small to medium size with, in the majority of cells, a small or invisible nucleolus. The cellular phenotype is very hetero- – A patient history, looking for any familial history of geneous, quite close to HCL-v, with a strong expression of haematological malignancy or autoimmune disorders; CD11c (97 %), a variable expression of CD103 (38 %) and – Identification of any systemic symptoms; little or no expression of CD123 (16 %) and CD25 (3 %). The – Checking for signs of disease, especially checking for blood karyotype may show anomalies such as 7q deletion. splenomegaly. The use of imaging can be helpful for this. The immunoglobulin variable heavy chain (IgVH)gene pro- Ultrasonography of the spleen can be used to measure the file is mutated in 80 % of cases, with over-represented use of size of the spleen and to identify abdominal lymphade- VH3–26 and VH4–34. The BRAF V600E mutation is absent nopathy, which is uncommon. in SRPL. Biological tests include the following: – A complete blood count with differential including a reticulocyte count; Required pretreatment evaluation – Serum protein electrophoresis to look for a monoclonal component; Assessment of prognostic factors – Haemolysis screen in the presence of suspicion. Unless there is a therapeutic indication, there is no justification The following is desirable: for carrying out any additional investigations for the assess- ment of prognostic factors. No prognostic factor will modify – Preservation of tumour material in blood and/or bone the choice of first-line treatment, which is based on purine marrow before any treatment. nucleoside analogues (PNAs): cladribine or pentostatin. 1980 Ann Hematol (2014) 93:1977–1983 Studies in patients treated with cladribine have resulted in Treatment the identification of factors, which may reduce the following Indications for treatment responses to treatment: Criteria for initiating treatment may vary depending on wheth- – Leukocytosis >10×10 /L [18] – Bulky spleen extending >10 cm below costal margin [18] er or not the patient is treated in a clinical trial. In general practice, treatment is indicated in the presence of at least one – Unmutated IgVH gene profile ≥98 % [18] – Use of the VH4–34 repertoire [19] of the signs of active disease as follows: – Mutation of the TP53 gene [18]. 1. Symptomatic splenomegaly Other factors reduce event-free survival (EFS) [18]as 2. Cytopenia (involving at least one cell type) follows: (a) Haemoglobin <10 g/dL (b) Platelets <100×10 /L – Bulky spleen extending >10 cm below costal margin – Elevated levels of circulating hairy cells >10×10 /L (c) Neutrophils <1×10 /L 3. Recurrent or severe infections – Unmutated IgVH profile. In the absence of treatment, clinical monitoring and mon- TP53 mutation testing and analysis of the IgVH gene repertoire to test for VH4–34 positivity must be performed itoring of the blood count are necessary every 3 months for the first year and then every 6 months. in the event of a relapse, before the second line of treatment, on previously frozen material or fresh material if possible. Treatment strategy Pretreatment assessment Inclusion in a prospective study protocol is recommended. In Parameters considered necessary for a complete pretreatment general practice, the recommendations are as follows. evaluation may differ depending on whether or not the patient is treated in a clinical protocol. First-line treatment The following are essential pretreatment tests (clinical trials and general practice): The first-line treatment is based on PNAs [20–22]: cladribine or pentostatin. The different dosing regimens for the two medicinal products are listed in Table 1. – Physical examination including the determination of the performance status as defined by the Eastern Cooperative There are no data in the literature proving the superiority of Oncology Group (ECOG) and the identification of co- one drug over the other. The choice between pentostatin and morbidities and potential sites of infection. cladribine is based essentially on the presence or absence of – Serum chemistry including creatinine with calculation of renal impairment, the severity of the cytopenias and the dosing creatinine clearance (Modification of Diet in Renal Dis- regimens of the products. Cladribine may be used intrave- ease (MDRD) Study), haemolysis screen (direct antiglob- nously (IV) or subcutaneously (SC), unlike pentostatin, which ulin test, haptoglobin, unconjugated bilirubin and lactic is used only via the IV route. The SC form offers ease of dehydrogenase) and liver function tests (transaminases) administration and the option of treatment on an outpatient basis, unlike cladribine IV. with hepatitis B and C serology (risk of reactivation after immunosuppressive therapy). In the presence of renal impairment (plasma creatinine clearance (MDRD) <60 mL/min), pentostatin is contraindi- – Preservation of cells and serum in a tumour bank is recommended. cated owing to limited experience, unlike cladribine. – Chest radiograph and abdominal and pelvic imaging. Special cases The following are additional pretreatment tests that may be performed in clinical trials: In cases of severe neutropenia (neutrophil count <0.2×10 /L) and/or uncontrolled active infection, the treatment of choice is – Blood and bone marrow karyotypes analysis. interferon via the SC route at a dose of 3 million units×3 per – BRAF V600E mutation testing. week followed by a purine analogue once the neutropenia has – Mutational status of IgVH gene and analysis of the VH been corrected. Another option, although not validated in this gene usage. indication, is the use of rituximab on its own at a dose of – Mutational status of TP53 gene. 375 mg/m IV for 4 weeks in the place of interferon. Ann Hematol (2014) 93:1977–1983 1981 Table 1 Different dosing regimens In cases of early relapse (<24 months), the diagnosis of HCL must be confirmed and BRAF V600E mutation testing Dosing regimen for cladribine (2-chlorodeoxyadenosine (2-CDA)) must be performed. Authorized dosages 0.14 mg/kg/day SC for 5 days 1. If the diagnosis of HCL is confirmed, the management 0.1 mg/kg/day as a continuous IV infusion for 7 days approach will depend on the presence or absence of a Other dosages (off-label) TP53 gene mutation and VH4–34 use. 0.14 mg/kg/day as an IV infusion over 2 h for 5 days 0.14 mg/kg/day IV once weekly for 6 weeks (a) In the absence of the TP53 gene mutation, with a VH repertoire other than VH4–34, the use of a PNA 0.14 mg/kg/day SC once weekly for 5 weeks combined with rituximab is recommended. Thedosagemust berepeated inthe absence ofCRat 6 months (b) In cases of TP53 gene mutation [25] and/or use of Dosing regimen for pentostatin in HCL (2′-deoxycoformycin (2′-DCF)) VH4–34, the different treatment options are as follows: 4 mg/m every 2 weeks until a maximal response is achieved, plus one or two additional injections Determine the creatinine clearance before each administration and – Immunotoxins, but they are not available in France avoid the medicinal product in the presence of clearance <60 mL/ [26,27]. min – BRAF inhibitors either alone or in combination with Dosing regimen for rituximab (4–8 doses in total) MEK inhibitors. No treatment regimen is defined at pres- 375 mg/m IVonce weekly administered simultaneously or ent [28–31]. The use of these treatments must take into sequentially with the purine analogue in patients without CR after a account the toxicity of these drugs, including their cuta- single treatment with pentostatin or cladribine neous effects [30,32,33]. Interferon alpha (IFN-α) 6 – Bendamustine and rituximab in combination [34]. 3×10 U SC daily until a maximal response is achieved and continuation at the same dose three times weekly. In very cytopenic – If access to innovative compounds is impossible, a com- patients, start on a dose of 3×10 U 3 times weekly bination of treatment with PNA and rituximab is Splenectomy recommended. Indicated in cases of bulky splenomegaly (>10 cm below the costal 2. If the diagnosis of HCL is not confirmed and in the margin) and in cases of moderate bone marrow involvement, after absence of a BRAF V600E mutation, an analysis of the immunization programme IgVH repertoire to test for VH4–34 use must be per- formed. Treatment must be considered on a case-by-case basis. In cases of active haemolytic anaemia, consideration might be given to rituximab. Subsequent relapses Some options used before the era of In cases of pregnancy, the only treatment that can be used is PNAs should not be ruled out, including splenectomy and interferon via the SC route at a dose of 3 million units×3 per interferon. week. In cases of two co-existing haematological disorders or a Prevention of infectious complications concomitant haematological disorder, the management ap- proach should be discussed at a multidisciplinary meeting. The prevention of infectious complications occurring during the course of HCL treatment or in the post-treatment period is Relapses of prime importance. In the prevention of Pneumocystis jiroveci-induced in- Only symptomatic relapses require treatment. fections with Bactrim® until recovery of T cell numbers to CD4>200/mm , there is an increased risk of allergic skin First relapse In cases of late relapse (>60 months), PNAs may reactions during concomitant use of Bactrim® with purine be used again. No recommendations exist regarding whether analogues. This risk can be reduced by starting Bactrim® or not the PNAs should be changed. 1 week after the purine analogue. In cases of allergy to Bactrim® or cytopenias potentially linked to Bactrim®, In cases of intermediate relapse (24–60 months), the Pentacarinat® or atovaquone (Wellvone®) aerosols may be second-line treatment also relies on PNAs, whether or not a used. different PNA is used and whether or not it is combined with Prevention of zoster infections with aciclovir or rituximab, administered concomitantly or sequentially (non- valaciclovir should also be started 1 week after PNAs. The validated treatment regimens) [23,24]. optimal duration of prophylaxis has not been determined. 1982 Ann Hematol (2014) 93:1977–1983 Open Access This article is distributed under the terms of the Creative Growth factors should be considered on a case-by-case Commons Attribution License which permits any use, distribution, and basis. reproduction in any medium, provided the original author(s) and the No data in the literature provide a basis for either source are credited. recommending or not recommending the irradiation of labile blood products after treatment with purine analogues. References 1. Bernstein L, Newton P, Ross RK (1990) Epidemiology of hairy cell Response criteria and evaluation leukemia in Los Angeles County. Cancer Res 50(12):3605–3609 2. Morton L, Wang S, Devesa S, Hartge P, Weisenburger D, Linet M The following definitive response should be assessed: (2006) Lymphoma incidence patterns by who subtype in the United States, 1992–2001. Blood 107(1):265–276. doi:10.1182/Blood- 2005-06-2508 – For pentostatin, at the end of treatment, after 8 to 3. Troussard X, Duchenet V, Cornet E, Mouchel D, Malet M, Collignon 10 cycles A (2009) Haematological malignancies: incidence in Basse- – For cladribine, 3 to 6 months after the end of treatment. Normandie, France, for 1997–2004. Rev Epidemiol Sante Publique 57(3):151–158. doi:10.1016/J.Respe.2009.02.204 4. Chandran R, Gardiner SK, Smith SD, Spurgeon SE (2013) Improved Complete remission (CR) is defined as follows: survival in hairy cell leukaemia over three decades: a seer database analysis of prognostic factors. Br J Haematol 163(3):407–409. doi: – Recovery of blood counts with haemoglobin >12 g/dL, 10.1111/Bjh.12490 9 9 5. Clavel J, Hemon D, Mandereau L, Delemotte B, Severin F, Flandrin platelets >150×10 /L, neutrophils >1.5×10 /L and ab- G (1996) Farming, pesticide use and hairy-cell leukemia. 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Annals of HematologyPubmed Central

Published: Jul 5, 2014

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