Multicenter retrospective analysis regarding the clinical manifestations and treatment results in patients with hairy cell leukemia: twenty-four year Turkish experience in cladribine

Hematological OncologyHematol Oncol (2014)Published online in Wiley Online Library(wileyonlinelibrary.com) DOI: 10.1002/hon.2177

Original Research Article

Multicenter retrospective analysis regarding the clinicalmanifestations and treatment results in patients with hairycell leukemia: twenty-four year Turkish experience incladribine therapy

Sibel Hacioglu1*, Yusuf Bilen2, Ali Eser3, Serdar Sivgin4, Emel Gurkan5, Rahsan Yildirim2, Ismet Aydogdu6,Mehmet Hilmi Dogu1, Mehmet Yilmaz7, Omur Kayikci8, Anil Tombak9, Irfan Kuku10, Harika Celebi11,Meltem Olga Akay12, Ramazan Esen13, Serdal Korkmaz14 and Ali Keskin11Pamukkale University, Department of Hematology, Denizli, Turkey2Ataturk University, Department of Hematology, Erzurum, Turkey3Marmara University, Department of Hematology, Istanbul, Turkey4Erciyes University, Department of Hematology, Kayseri, Turkey5Cukurova University, Department of Hematology, Adana, Turkey6Celal Bayar University, Department of Hematology, Manisa, Turkey7Gaziantep University, Department of Hematology, Gaziantep, Turkey8Ankara Oncology Education and Research Hospital, Department of Hematology, Ankara, Turkey9Mersin University, Department of Hematology, Mersin, Turkey10Inonu University, Department of Hematology, Malatya, Turkey11Diskapi Yildirim Beyazit Education and Research Hospital, Department of Hematology, Ankara, Turkey12Osmangazi University, Department of Hematology, Eskisehir, Turkey13Yuzuncu Yil University, Department of Hematology, Van, Turkey14Cumhuriyet University, Department of Hematology, Sivas, Turkey

*Correspondence to: SibelHacioglu, MD, PamukkaleUniversity, Faculty of Medicine,Department of Hematology,20070 Denizli, Turkey.E-mail: [email protected]

Received 25 July 2014Revised 2 October 2014Accepted 3 October 2014

Copyright © 2014 John Wiley & Son

AbstractIn this multicenter retrospective analysis, we aimed to present clinical, laboratory and treat-ment results of 94 patients with Hairy cell leukemia diagnosed in 13 centers between 1990and 2014. Sixty-six of the patients were males and 28 were females, with a median age of55. Splenomegaly was present in 93.5% of cases at diagnosis. The laboratory findings thatcame into prominence were pancytopenia with grade 3 bone marrow fibrosis. Most of thepatients with an indication for treatment were treated with cladribine as first-line treatment.Total and complete response of cladribine was 97.3% and 80.7%. The relapse rate aftercladribine was 16.6%, and treatment related mortality was 2.5%. Most preferred therapy(95%) was again cladribine at second-line, and third line with CR rate of 68.4% and66.6%, respectively. The 28-month median OS was 91.7% in all patients and 25-month me-dian OS 96% for patients who were given cladribine as first-line therapy. In conclusion, thefirst multicenter retrospective Turkish study where patients with HCL were followed up fora long period has revealed demographic characteristics of patients with HCL, and confirmedthat cladribine treatment might be safe and effective in a relatively large series of the Turk-ish study population. Copyright © 2014 John Wiley & Sons, Ltd.

Keywords: hairy cell leukemia; Turkey; treatment; cladribin; survival

Introduction

Hairy cell leukemia (HCL) is part of the low-grade non-Hodgkin lymphoma family and represents approximately2% of all types of leukemia. According to the case seriesin literature, the majority of patients present with pancyto-penia and splenomegaly with associated fatigue, left upperquadrant abdominal pain, fever and infections, and/orbleeding problems [1].

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Treatment with splenectomy and interferon-α histori-cally belonged to the first steps of therapeutic options,achieving partial responses/remissions in most caseswith a median survival between 4 and 6 years in the1980s. The introduction of the purine analogs—especially cladribine—made HCL a well-treatabledisease. Overall complete response rates (CRR) rangefrom 76 to 98%, with a median disease-free survival(DFS) of 16 years [2].

S Hacioglu et al.

In this paper, we aimed to present the first report of mul-ticenter experience regarding the clinical and treatment re-sults of the patients with hairy cell leukemia in our countrythat may reflect the outcomes of the disease in Eastern Eu-rope and the middle East.

Material and methods

Patients

One hundred and fifty-six files of the HCL patients in 13centers were reviewed. However, 62 patients with missingdata were excluded. Therefore, a total of 94 patients be-tween October 1990 and January 2014 were retrospec-tively evaluated in this report. The study was approvedby the local Ethics Committees and was in accordance withthe Declaration of Helsinki.

Diagnosis of disease

A diagnosis of HCL was established according to WHOcriteria by morphological and flow cytometric analysis ofperipheral blood, bone marrow and/or spleen specimens [3].

Criteria of treatment initiation and cladribine doses

Those patients who had neutropenia (absolute neutrophilcount of <1.0 × 109/L), anemia (hemoglobin <10 g/dL),thrombocytopenia (platelets <100×109/L), symptomaticsplenomegaly or recurring infections were treated. Thesame criteria were used in patients in whom the disease re-lapsed. Cladribine was administered intravenously as acontinuous infusion at doses of 0.14mg/kg/day and0.09mg/kg/day for 5 and 7 consecutive days, respectively.

Response criteria and definition of relapse

Response was evaluated with morphological andimmunephenotyping of peripheral blood and bone marrowbiopsy 3months after treatment. Consensus Resolution [4]was used for response criteria. According to this, a Com-plete Remission (CR) was defined as absence of morpho-logical hairy cells (HCs) in blood and bone marrow andresolution of organomegaly and cytopenias. Partial Remis-sion (PR) was defined as the complete blood count returnto normal of blood count, at least 50% decrease inorganomegaly and HC infiltration in the bone marrow,and circulating HCs <%5. All other cases were consideredas unresponsive. In addition, relapse after CR was definedas reoccurrence of HCs in the peripheral blood or bonemarrow, cytopenia and/or splenomegaly on physical exam-ination. Relapse after PR was defined as >%50 increase inresidual disease.

Copyright © 2014 John Wiley & Sons, Ltd.

Survival analysis

Relapse free survival (RFS) was defined as time from thestart of treatment to relapse. Overall survival (OS) was de-fined as time from start of treatment to either (a) death froman unknown or any reason or (b) death from HCL. Allother cases were considered event-free until the end ofthe follow-up period.

Statistical analysis

All statistical analyses were performed using SPSS version20.0 (SPSS, Chicago, IL, USA). Descriptive statistics werecalculated for each of the variables. Data were expressed asmean± standard deviation (SD) (normally distributeddata), median and interquartile range (IR) (non-normallydistributed data), or as percentage frequencies. For survivalanalysis, univariate Kaplan–Meier analysis were per-formed. Differences among variables were evaluated bythe Pearson Chi-square test. P values of less than 0.05 wereregarded as significant.

Results

Patient characteristics

Sixty-six of the patients were males and 28 females (male/female ratio: 66/28= 2.3), and the median age was 55(range: 30–83). Of the 94 patients included in the study,5 (5.3%) had variant HCL. The main clinical features ofthe patients are presented in Table 1, and laboratory find-ings are presented in Table 2.

Treatment results

Eighty-six percent (75/87) of the patients were treated.Four died before treatment, and 3 were lost duringfollow-up among the remaining patients. In all patients,the median time between diagnosis and start of treatmentwas 30 days (range: 4–2500days).

In 89.6% of patients with an indication for treatment(78/87), first-line treatment was cladribine, while splenec-tomy was selected in 6.8% (6/87) and interferon was usedin 3.4% (3/87).

In first line therapy, CR was obtained in 80.7% (63/78)of the patients treated with cladribine, PR was obtainedin 16.6% (13/78) (overall response rate 97.3%) and 2 pa-tients (2.5%) were lost during treatment. CR was obtainedin 66.7% (4/6) of the patients treated with splenectomy andPR was obtained in 33.3% (2/6). There were no deaths inthis group. The responses in 3 patients treated with IFNwere only PR.

Thirteen patients (16.6%) relapsed after their first courseof cladribine. Of these, 10 patients had achieved a prior

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Table 1. Clinical characteristics of patients

Characteristic n (%)

GenderMale 66 (70)Female 28 (30)

Age (years) (median, range) 55 (30–83)

Symptoms at admissionFatigue 24 (25.5)Fever, findings of infection 15 (15.9)Findings of bleeding 12 (12.7)Early satiety, gas in stomach 9 (9.5)Weight loss, sweating, fever 9 (9.5)Incidentally 25 (26.5)

SplenomegalyNo splenomegaly 6 (6.3)Mild (≤18 cm) 50 (53.1)Massive (>18 cm) 38 (40.4)

HepatomegalyNo hepatomegaly 20 (21.2)14–17 cm 42 (44.6)17–20 cm 25 (26.5)≥20 cm 7 (7.4)

LymphadenopathyNo lymphadenopathy 75 (79.7)Local 13 (13.8)Disseminated 6 (6.3)

able 2. Baseline laboratory characteristics of patients

arameter Median (range)

b (g/dL) 9.0 (3.0–15.2)latelets (×109/L) 64.0 (10–408.0)BC count (×109/L) 3.5 (0.55–82.0)

ymphoctes (×109/L) 1.6 (0.24–74.0)onocytes (×109/L) 0.2 (0–42.4)

arameter n (%)

nemia (Hb< 12.0 g/dL) 72 (77.6)hrombocytopenia (Plt< 100× 109/L) 71 (75.5)eukopenia (WBC< 4× 109/L) 53 (56.3)eukocytosis (WBC> 10× 109/L) 17 (18.0)onocytopenia (<0.1 × 109/L) 40 (42.5)

t the time of diagnosisBicytopenia 32 (34.0)Pancytopenia 44 (46.8)

one marrow infiltration typeDiffuse infiltration 65 (73.0)Nodular infiltration 14 (15.7)Interstitial infiltration 10 (11.2)

he grade of fibrosisGrade 0 fibrosis 6 (7.7)Grade 1 fibrosis 9 (11.6)Grade 2 fibrosis 22 (28.5)Grade 3 fibrosis 31 (40.2)Grade 4 fibrosis 9 (11.6)

munophenotypic analysisCD 19 89 (96.4)CD 20 88 (95.0)CD 22 90 (97.0)CD 25 70 (75.0)CD 11c 87 (94.0)CD 103 87 (94.0)

RAP positivity 92 (97.8)

b: Hemoglobin, WBC: White blood cell, Plt: Platelets, CD: Clusterf differentiation, TRAP: Tartrate resistant acid phosphatase.

Figure 1. OS curve in all patients included in this study

Hairy cell leukemia in Turkey

complete response and 3 patients had achieved a prior par-tial response. The median time to first relapse after the firstcourse of cladribine was 24months for all responders. Pa-tients who had achieved a prior complete response had amedian time to first relapse of 36months, and patientswho had achieved a prior partial response had a mediantime to first relapse of 6months.In second-line treatment, cladribine was used in 95%

(19/20) and rituximab was used in only one (5%) patient.CR was obtained in 68.4% (13/19) of patients treated withcladribine as second-line treatment, and PR was obtainedin 31.5% (6/19) of this group. A second relapse developedin 31.5% (6/19) of these patients. The median time to sec-ond relapse was 60months in all these patients.In third-line treatment, 3 of these 6 patients (50%) were

given cladribine again, 2 (33.3%) were given rituximaband 1 was given (16.6%) deoxycoformycin. The rate ofCR with third-line cladribine was 66.6% (2/3), and rateof PR was 33.3% (1/3).The median OS duration has not been reached with a me-

dian follow-up of 28months (range: 1– 228). The overallsurvival rate was 82.8% recorded at 228months (Figure 1).Survival at 5 years from start of cladribine at first line treat-ment is 96% (Figure 2). A total of eight deaths (8.5%) havebeen registered. Four of these patients were variant HCLand died due to progressive disease. The remaining four pa-tients died due to sepsis before chemotherapy, aspergillus


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Discussion

Figure 3. Survival analysis between HCL-C and HCL-V

Figure 2. OS curve of patients given cladribine as first-linetreatment

able 3. The correlation of complete blood count parametersnd degree of bone marrow fibrosis with response rates

arameters n CR/PR/ex p

BC (mm3) <1500 15 12/3/0 0.7451501–3500 26 23/2/1

3501–10 000 24 19/5/0>10 001a 13 9/3/1

onocyte (mm3) <50 22 17/5/0 1.051–100 11 9/2/0101–200 8 6/1/1

201–1000 19 16/2/1>1001 18 15/3/0

emoglobin (g/dL) <6 5 4/1/0 0.6926.1–9.0 34 28/5/19.1–12.0 21 17/3/1

>12.1 18 14/4/0latelet (×109) <25 7 3/3/1 0.054

26–50 22 18/3/151–100 31 28/3/0>101 18 12/4/0

egree of fibrosis (grade) Grade 0 5 3/1/1 1.0Grade 1 9 6/3/0Grade 2 22 19/3/0Grade 3 31 26/4/1Grade 4 9 7/2/0

The response to treatment was worse in patients who had leuko-ytosis at admission (p=0.014).

S Hacioglu et al.

infection during cladribine therapy, development of acutemyeloid leukemia and acute myocardial infarction aftertreatment, respectively. Compared to classical HCL,variant HCL had significantly shorter overall survival(p< 0.0001) (Figure 3).We did not determine an effect of hemoglobin level

(p=0.692), leukocyte count (p=0.745), monocyte count(p=1.0), the degree of splenomegaly (p=0.767), type ofbone marrow infiltration (p=0.985) and degree of bone mar-row fibrosis (p=1.0) on treatment failure (Table 3). Althougha low platelet count was associated with a poor prognosis, itdid not reach significance (p=0.054). While the response totreatment was worse in patients who had leukocytosis at ad-mission (p=0.014), there was no association between treat-ment results and cytopenia in one cell-line (p=0.718),bicytopenia (p=0.920) and pancytopenia (p=0.9).


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HCL constitutes 2–3% of all adult leukemias [5,6]. It ischaracterized with infiltration of bone marrow, liver,spleen and rarely lymph nodes with malignant B-cell withhair like cytoplasmic projections [7]. The age when this ill-ness occurs is frequently in the fifth decade of life, and it is4–6 times more frequently seen in males [1,8,9].

Treatment is indicated in HCL patients with prominentneutropenia, symptomatic splenomegaly and constitutionalsymptoms due to HCL or recurring infections [10]. A Hblevel below 11.0gr/dL, thrombocyte level below 100×109/L or neutrophil count below 1×109/L is reported to be an in-dication for treatment in some papers [11,12]. A bulky and/orpainful lymphadenopathy, leukocytosis (leukocyte count>20×109/L), disease related vasculitis and bone involve-ment are among other indications for treatment [10]. The de-cision to treat was due to cytopenia and/or symptoms relatedwith cytopenia in 86% of our patients, while 8.1% weretreated due to hypermetabolic symptoms such as fever, nightsweats and weight loss, and 5.8% were treated due to symp-toms caused by a massive splenomegaly.

The developments in the treatment of HCL in the last 2decades, and the 4 new medications—alpha interferon, 2′-deoxycoformycin, 2-chlorodeoxyadenosine and rituximab—have somewhat improved survival [9]. The rate of CRis nearly 80–90% with nucleoside analogues, cladribineand pentostatin [13,14].


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This study provides an opportunity to evaluate the re-sponses to treatment with cladribine as first-line, second-line and third-line treatment in a multicenter but retrospec-tive setting in the Turkish population. The initial responserate with the first course of cladribine was 97.3%, and themajority of responses were complete responses (80.7%).The results reported confirm previous observations thatcladribine administered to patients with HCL induces highresponse rates [9,15–22]. In 1998, Saven et al. [17] ob-tained a CR in 91% of their patients and a PR in 7% inthe first treatment with cladribine, and reported relapse in26% of them in a median time of 29months, a CR in62% and a PR of 26% in their second use of cladribine,in their study evaluating the results in 358 HCL patientstreated with cladribine.Other groups have reported similar results. Goodman

et al. [18] reported a CR at first treatment in 95%, a PRin 5%, with an overall response (OR) of 100%, and98months of median first response in all responders intheir study of 209 HCL patients who were treated withcladribine and were followed up for at least 7 years. Re-lapse developed in 37% of the patients, 79% of whom weretreated with cladribine for a second time and a CR was ob-tained in 75%, a PR in 17% and failure in 8%. Hoffmanet al. [23] described the experiences of 49 HCL patientstreated with cladribine. The first complete response ratewas 76%, and the partial response rate was 24% (overallresponse rate: 100%). The median follow-up durationwas 55months. The relapse-free survival rate was 80%,and the overall survival rate was 95%.In the literature, the 5-year progression-free survival

(PFS) rates vary between 72 and 84%, and the OS at12years vary between 75 and 87% [24] with cladribinetreatment. The risk of relapse at 4 years amounts to approx-imately 30% [25]. This study where patients with HCL werefollowed up for a long period has confirmed that cladribinetreatment might be safe and effective. The outcome of thesepatients is excellent, with an overall survival rate of 96% at5years, and these rates may suggest that most patientstreated with cladribine may expect a normal life span.In the preliminary results of Else et al. [26] in their patient

series with HCL, patients who had obtained a CR had longerrelapse free survival than patients obtaining a PR, with a pro-gressively decreasing CR rate in second and third treatments.These findings are in accordance with other series[10,19,20,27,28], which includes that persistence on treat-ment is important until a CR is obtained, if toxicity is notpresent, and the outcome should be evaluated with bone mar-row biopsy and follow-up of minimal residual disease. FirstCR showed a decrease in second and third treatments in ourstudy with cladribine treatment (a CR rate of 80.7% at firstline treatment, 68.4% at second line treatment and 66.6% atthird line treatment), without a significant difference inrelapse-free survival durations (first RFS 36months, secondRFS 60months, third RFS has not been reached yet).


In our case series, a CR was obtained in the 2 patientswith a 2nd line cladribine, in whom a PR could be obtainedat the first cladribine use. In one of these patients, relapseoccurred after 8months of follow-up at partial remissionafter a first treatment with cladribine and a need for a 2nd

cladribine treatment had occurred. After obtaining a CRwith this 2nd use of cladribine, relapse occurred after48months of follow-up. In the second patient, relapsehad occurred after 6months of follow-up at partial remis-sion after the first cladribine treatment, and a 2nd cladribinetreatment was necessary. After the 2nd cladribine treatment,CR was obtained, and the patient is still at remission after38months of follow-up. This data also supports Elseet al. [9] in that obtaining a CR was harder at the followingtreatment each time, but still, if it is reached, relapse freesurvival time may be equal independent of the fact that thiswas the first, second or third line of treatment and relapsefree survival may be better when the response is CR.In the studies related with HCL, poor response to treatment

was found to be associated with advanced age, low levels ofhemoglobin, low platelet count, splenectomy, lymphadenop-athy, leukopenia, leukocytosis, presence of prior treatment(s), short time period between diagnosis and treatment, anda low performance status [10,16,17,27–31]. On the otherhand, unlike these studies, the response to treatment wasworse only in patients that presented with leucocytosis inour study. We did not demonstrate any effects of other pa-rameters that were given in the results section.Another problem in patients with HCL is the increased

risk of occurrence of a solid cancer. This rate is reportedbetween 2% and 19% in different patient series [32,33].The increased risk of secondary cancer was found to be as-sociated with advanced age and diagnosis of cancer beforediagnosis of HCL. Disruption of T cell functions and natu-ral killer cells due to cladribine in HCL were claimed to in-crease the risk of secondary cancer development [34–36].On the other hand, Cheson et al. [35] reported no associa-tion between secondary cancer development and eithercladribine or pentostatin use. In a population based study[37], the risk of a secondary cancer development was31.9% in 3104 patients with HCL, which represented a1.24 times increase in secondary cancer development,among which the most prevalent were Hodgkin’s lym-phoma, non-Hodgkin’s lymphoma and thyroid cancer. Inthe present study, two patients were diagnosed as havinglung cancer and timoma before HCL was diagnosed, andanother patient was diagnosed as having acute leukemia3months after HCL diagnosis and treatment.Our study suffers from all the limitations of retrospective

analyses, including the lack of uniformity in the diagnosisand management of the underlying disease and its compli-cations. Nonetheless, this is the largest study published todate regarding the clinical manifestations and results ofcladribine therapy in patients with HCL in our country.Therefore, these results may indicate that at least the


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S Hacioglu et al.

clinical course of Turkish patients with HCL is similar tothe results reported from western countries.In conclusion, the current multicenter retrospective

study where patients with HCL were followed up for along period has revealed demographic characteristics ofthese patients, and confirmed that cladribine treatmentmight be safe and effective in a relatively large series ofthe Turkish study population. A majority of the patientswere followed up at CR after treatment with cladribine,and it is suggested that successful results may be obtainedwith cladribine treatment again in patients with a relapse.The long-term follow-up is also important for the evalua-tion of the development of secondary malignancies.

Conflict of interest

The authors report no conflicts of interest. The authors aloneare responsible for the content and writing of the paper.

Acknowledgements

We would like to thank Beyza Akdağ for the statistical analysis ofthe study, and also Ali Unal, Bulent Eser, Cengiz Demir, EminKaya, Emre Tekgunduz, Fatih Kurnaz, Fevzi Altuntas, HasanKaya, Ilhami Kiki, Ismail Sari, Leylagul Kaynar, MehmetGundogdu, Mehmet Sencan, Mehmet Ali Erkurt, Naci Tiftik,Orhan Ayyildiz and Osman Ilhan (in alphabetical order) for serv-ing as our mentors in the Anatolian study group.

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DOI: 10.1002/hon

Multicenter retrospective analysis regarding the clinical manifestations and treatment results in patients with hairy cell leukemia: twenty-four year Turkish experience in cladribine

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