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Retrospective Evaluation of Hairy Cell Leukemia Patients Treated with Three Different First-Line Treatment Modalities in the Last Two Decades: A Single-Center Experience

Retrospective Evaluation of Hairy Cell Leukemia Patients Treated with Three Different First-Line... Öz Objective: In this study, we retrospectively analyzed the clinical Amaç: Bu çalışmada, geriye dönük olarak 71 tüylü hücreli lösemi (SHL) outcome, treatment responses, infectious complications, and survival olgusunu klinik sonuçlar, tedavi yanıtları, enfeksiyon komplikasyonları rates of 71 hairy cell leukemia (HCL) cases. ve sağkalım oranları açısından analiz ettik. Materials and Methods: Sixty-seven patients received a first-line Gereç ve Yöntemler: Altmış yedi hasta birinci basamak tedavi almıştı treatment and 2-chlorodeoxyadenosine (cladribine-2-CdA) was ve 2-klorodeoksiadenozin (kladribin-2-CdA) 31 olguya uygulanmış, 19 administered in 31 cases, 19 patients received interferon-alpha hasta interferon-alfa (INF-α) almış, splenektomi 16 olguda uygulanmış (INF-α), splenectomy was performed in 16 cases, and rituximab was ve rituksimab ise bir hastada kullanılmıştı. used in one. Bulgular: En yüksek toplam yanıt oranı (TYO) birinci basamak 2-CdA Results: Although the highest overall response rate (ORR) was alan hastalarda görülmüş olsa da, TYO’lar 2-CdA, INF-α ve splenektomi observed in patients receiving 2-CdA upfront, ORRs were comparable alt gruplarında benzerdi. Nüks oranları birinci basamak 2-CdA alan in the 2-CdA, INF-α, and splenectomy subgroups. Relapse rates were hastalarda anlamlı olarak daha azdı. Progresyonsuz sağkalım (PS) oranı significantly lower in patients who received first-line 2-CdA. The 2-CdA alanlarda INF-α ve splenektomi hastalarına göre anlamlı olarak progression-free survival (PFS) rate with 2-CdA was significantly daha yüksek olmakla birlikte, her üç birinci basamak tedavi yaklaşımı higher than in patients with INF-α and splenectomy, but we found ile toplam sağkalım (TS) oranları benzer olarak bulundu. Tüberkülozun similar overall survival rates with all three upfront treatment da dahil olduğu enfeksiyonlar önemli bir problemdi. modalities. Infections including tuberculosis were a major problem. Sonuç: Her ne kadar pürin analogları TYO ve PS’yi iyileştirmiş olsa da, Conclusion: Although purine analogues have improved the ORRs and SHL hastalarında TS ve nüks/dirençli hastalık açısından daha yapılması PFS, there is still much progress to make with regard to overall survival gereken çok şey vardır. and relapsed/refractory disease in patients with HCL. Anahtar Sözcükler: Kladribin, Tüylü hücreli lösemi, İnterferon, Keywords: Cladribine, Hairy cell leukemia, Interferon, Splenectomy Splenektomi Most patients eventually require therapy owing to worsening Introduction cytopenias, frequent and life-threatening infections, and/ Hairy cell leukemia (HCL) is a rare mature B-cell neoplasm or symptomatic splenomegaly. Several treatment modalities, characterized by the accumulation of atypical lymphocytes including splenectomy and immunotherapy with interferon- with prominent cytoplasmic projections in the bone marrow and spleen, resulting in pancytopenia and splenomegaly [1,2]. alpha (INF-α), were used with various clinical and hematologic ©Copyright 2017 by Turkish Society of Hematology Turkish Journal of Hematology, Published by Galenos Publishing House Address for Correspondence/Yazışma Adresi: Şeniz ÖNGÖREN, M.D., Received/Geliş tarihi: November 10, 2016 İstanbul University Cerrahpaşa Faculty of Medicine, Department of Hematology, İstanbul, Turkey Accepted/Kabul tarihi: July 26, 2017 Phone : +90 532 334 16 64 E-mail : senizongoren@hotmail.com ORCID-ID: orcid.org/0000-0002-2809-5510 291 Öngören Ş, et al: First-Line Treatment in Patients with HCL Turk J Hematol 2017;34:291-299 responses until the introduction of the purine nucleoside disappearance of hepatosplenomegaly and cytopenias. analogues 2-chlorodeoxyadenosine (cladribine, 2-CdA) and Normalization of peripheral blood counts together with an at least 50% reduction in the size of organomegaly and the volume 2′-deoxycoformycin (pentostatin) [3,4,5]. Purine analogues of bone marrow HCs, plus <5% circulating HCs, was designated have resulted in higher complete response (CR) rates and as partial response (PR). Presence of CR or PR was defined as durable remissions, and they have become the treatment of overall response (OR), and any response other than a CR or PR choice in most cases [6]. Monoclonal antibodies (i.e. rituximab) was considered as no response. During response evaluation, a and immunotoxins are currently recommended for relapsed/ bone marrow biopsy was performed 3 months after finishing refractory (R/R) cases [7,8,9]. Also among the target-oriented 2-CdA treatment. Furthermore, relapse after CR was defined as therapeutic options, the BRAF inhibitor vemurafenib can be the reappearance of HCs in the peripheral blood or bone marrow, used in patients with R/R HCL [10,11]. development of cytopenias, and/or splenomegaly on physical In this study, we retrospectively analyzed the clinical outcome, examination. Relapse after PR indicated a >50% increase of treatment responses, infectious complications, and survival rates residual disease. of HCL patients treated in our institution with three treatment Overall survival (OS) denotes the time from the first treatment modalities (splenectomy, INF-α, and 2-CdA) as first-line therapy until the time of death or last follow-up. The duration of between 1991 and 2014. progression-free survival (PFS) was calculated from the onset of any first-line treatment until the date of progression. Time to Materials and Methods next treatment (TTNT) was calculated as the time from the end Patients of the previous treatment to the institution of the next therapy. A total of 71 patients with HCL, who were diagnosed and Statistical Analysis followed in our clinic over the past 20 years, were included in this Student’s t-test was used for the comparison of the quantitative study. Diagnosis of HCL was established by morphological, flow- variables. Qualitative variables between groups were compared cytometric, and immunohistochemical analysis of peripheral using the chi-square test. The Kaplan-Meier method was used blood, bone marrow, and/or spleen specimens. Information on for survival analysis [13]. Survival rates were compared by the patients’ characteristics, presenting signs and symptoms, using the log-rank test. All tests were two-sided, and p<0.05 treatment modalities and outcomes, and infections were was considered as statistically significant. All analyses were retrospectively taken from the patients’ files. While defining the performed with SPSS 13.0 for Windows (SPSS Inc., Chicago, IL, patient cohort, we excluded cases with variant HCL. USA). Treatment Modalities Results Patients were divided into 3 subgroups according to the first-line treatments (i.e. splenectomy, INF-α, and 2-CdA) Sixty-two patients (87%) were male and the median age was 49 that they had received. Splenectomy was performed either years (range: 31-76 years). There were 53 patients (75%) with laparoscopically or via open surgery. 2-CdA was given either splenomegaly, and the numbers of patients with hepatomegaly by continuous intravenous infusion at a dose of 0.1 mg/kg/ and lymphadenopathy were 32 (45%) and 27 (38%), respectively. day over 7 consecutive days, or by 2-h intravenous infusion The demographic features of the entire cohort including median at a dose of 0.1 mg/kg once a week for 7 consecutive weeks, leukocyte and platelet counts and hemoglobin levels at diagnosis depending on whether the patients received it as an inpatient or are displayed in Table 1. The median duration of follow-up was outpatient treatment, respectively. While on 2-CdA, the patients 57 months (range: 1-217 months). At diagnosis, all patients were given cotrimoxazole prophylaxis against Pneumocystis had bone marrow biopsy, and flow cytometric evaluation was jirovecii pneumonia. INF-α was administered subcutaneously at performed for 47 patients (66%) from peripheral blood and/ a starting dose of 3 MU 3 times a week and maintained with or bone marrow. At diagnosis, hematoxylin and eosin staining, subsequent toxicity-based dose adjustments. Rituximab was reticulin staining, tartrate-resistant acid phosphatase staining, administered at the conventional dose of 375 mg/m weekly for and immunohistochemistry for CD20 and annexin A1 were 4 consecutive weeks, as suggested before [7]. performed from the bone marrow aspiration and trephine biopsy. Definition of Response and Survival Treatments and Outcomes Among the patient cohort, there were 4 patients who did not Response to treatment was assessed using the criteria described in the consensus resolution of 1987 [12]. Accordingly, CR was receive treatment. Two of them were lost to follow-up, one defined as the morphological absence of hairy cells (HCs) patient died due to severe infection, and one had an acute in the blood and the bone marrow in addition to complete myocardial infarction (AMI) and died before any treatment was 292 Turk J Hematol 2017;34:291-299 Öngören Ş, et al: First-Line Treatment in Patients with HCL initiated (Figure 1). were 97%, 84%, and 81%, respectively, and although the ORR of 2-CdA treatment was superior to those of the other 2 groups, First-Line Treatment the differences were not significant (Figure 2). During the first- line treatment, 2 patients (one on 2-CdA and one on INF-α) died Sixty-seven (94%) patients received a first-line treatment. due to infection (Figure 1). No postoperative complications were 2-CdA was administered for 31 patients (46%), 19 patients observed in patients with splenectomy. (28%) received INF-α, splenectomy was performed in 16 cases (24%), and rituximab was used in one case (2%) (Figure 1). Five of the 31 patients who received 2-CdA as the first-line Although patients in the splenectomy arm were younger than therapy required a second-line treatment after a median TTNT those in the other 2 arms, the differences were not statistically of 23 months (range: 3-58 months) (Table 2). There were 10 significant (Table 2). The 3 treatment subgroups were equally patients in the first-line INF-α subgroup who progressed and balanced regarding sex distribution, median hemoglobin levels, needed a second-line treatment following a median TTNT of 21 and leukocyte and platelet counts (Table 2). There were 30, 16, months (range: 1-96 months). Eleven of the 16 patients who and 13 patients who achieved OR after the first-line treatment underwent first-line splenectomy received a second-line therapy due to relapsed disease at a median TTNT of 5 months (range: with 2-CdA, INF-α, and splenectomy, respectively (Figure 1). The 2-73 months). Relapse rates were significantly lower in patients OR rates (ORRs) in the 2-CdA, INF-α, and splenectomy subgroups who received first-line 2-CdA than those who were treated with INF-α or splenectomy (p=0.007 and p<0.0001, respectively). However, this was not significantly different when the INF-α and splenectomy subgroups were compared (p=0.339) (Table 2). Although the patients with first-line splenectomy had a shorter median TTNT than those with 2-CdA and INF-α, the difference did not reach statistical significance (Table 2). The only patient who received rituximab as frontline treatment remained refractory to that therapy, and she needed further treatment. Second-Line Treatment With a median TTNT of 13 months (range: 1-96 months), 27 patients required a second-line treatment due to R/R disease. Figure 1. The distribution of first-line treatment modalities and Twelve patients received INF-α, 11 patients were treated with outcomes. 2-CdA, 3 patients underwent splenectomy, and one received 2-CdA: Cladribine, HCL: hairy cell leukemia, INF-α: interferon-alpha, RTX: rituximab, SPL: splenectomy, ORR: overall response rate, NRR: non-response rate. fludarabine. *See text for details. Eight and 2 of the 12 patients who received second-line INF-α had been initially treated with splenectomy and 2-CdA, Table 1. The baseline characteristics of the patients. Parameter  Entire cohort (n=71)  Sex - male/female, n (%)  62 (87)/9 (13) Median age, years (min-max)  49 (31-76) Median leukocyte count, x10 /L (min-max)  3.0 (0.5-9.4) Median hemoglobin level, g/dL (min-max) 10 (4-17) Median platelet count, x10 /L (min-max)  51.5 (21-124) Splenomegaly - yes/no, n (%) 53 (75)/18 (25) Mean spleen size, cm (min-max)* 11.4 (2-26) Hepatomegaly - yes/no, n (%)  32 (45)/39 (55) Lymphadenopathy - yes/no, n (%)  27 (38)/44 (62) Figure 2. Response rates according to the different first-line treatment modalities. Median follow-up duration, 57 (1-217) *2-CdA vs. INF-α; **2-CdA vs. splenectomy; ***INF-α vs. splenectomy. months (min-max)  *Spleen size was measured by physical examination and stated as the distance from ORR: Overall response rate, NRR: non-response rate, 2-CdA: cladribine, INF-α: the left costal margin in cm. interferon-alpha. 293 Öngören Ş, et al: First-Line Treatment in Patients with HCL Turk J Hematol 2017;34:291-299 respectively. In the remaining 2 patients the previous treatment Third-Line Treatment was also INF-α. The ORR was 100% in patients who received There were 6 patients who needed third-line treatment. INF-α, second-line INF-α, with only 3 patients requiring a third-line 2-CdA, and rituximab were used for 3, 2, and one of them, treatment due to relapsed disease. respectively, following a median TTNT of 36 months (range: 8-63 months). Among patients receiving third-line INF-α, one In patients who had 2-CdA as a second-line treatment, 7 had achieved and maintained CR throughout the entire follow-up. received INF-α as the first-line therapy, and 2 had splenectomy. The other 2 remained refractory to INF-α treatment; one died, The other 2 had been treated with rituximab and 2-CdA previously. and the other patient proceeded to fourth-line treatment. One All the patients responded to second-line 2-CdA (the ORR was of the 2 patients who received 2-CdA as a third-line treatment 100%), and only one relapsed after a follow-up of 48 months. achieved and maintained CR and the other patient died due to refractory disease. Splenectomy was performed in 3 patients as a second-line treatment. All of them initially responded to splenectomy; The patient who received third-line weekly rituximab could not th however, 2 needed further treatment due to relapsed disease. complete the 4 week of treatment due to an allergic reaction, rd The patient who received fludarabine as a second-line therapy which had happened following the 3 dose of the drug, and had achieved PR but was then lost to follow-up after 9 months. to proceed to fourth-line therapy. Table 2. Patient characteristics and treatment outcomes in patients with 3 first-line treatment options. First-Line Treatment (n=67) Parameter 2-CdA INF-α Splenectomy p value (n=31) (n=19) (n=16) Sex - male/female, n (%) 27 (87)/4 (13) 18 (95)/1 (5) 14 (88)/2 (12) 0.387* 0.969** 0.453*** Median age, years (min-max) 52 (33-75) 50 (33-76) 47.5 (31-64) 0.564* 0.094** 0.061*** Median leukocyte count, x10 /L (min-max) 3.1 (1.6-7.2) 3.0 (0.5-9.4) 3.4 (0.5-9.1) 0.601* 0.510** 0.392*** Median hemoglobin level, g/dL (min-max) 11 (5-17) 10 (4-14) 9 (5-15) 0.098* 0.053** 0.721*** Median platelet count, x10 /L (min-max) 62 (22-108) 42.5 (21-124) 56 (29-81) 0.624* 0.552** 0.888*** Patients needing further treatment(s) due to R/R disease, n (%) 5 (16) 10 (53) 11 (69) 0.007* <0.0001** 0.339*** Median TTNT, months (min-max) 23 (3-58) 21 (1-96) 5 (2-73) 0.902* 0.370** 0.190*** Median follow-up, months (min-max) 53 (5-213) 57 (2-154) 83 (15-217) 0.739* 0.120** 0.230*** One patient received rituximab as a first-line treatment, *2-CdA vs. INF- α; **2-CdA vs. splenectomy; ***INF-α vs. splenectomy. R/R: Relapsed/refractory, TTNT: time to next treatment, 2-CdA: cladribine. 294 Turk J Hematol 2017;34:291-299 Öngören Ş, et al: First-Line Treatment in Patients with HCL Fourth-Line Treatment drug-resistant disease, and none of them had any known comorbidities including diabetes. There were also 2 patients There were only 2 patients who received a fourth-line with invasive pulmonary aspergillosis (IPA). treatment. One of them was treated with INF-α and the other with rituximab. The patient who received INF-α died due to Six of the 10 episodes of viral infections were related to flu. One refractory disease, and the patient who was given rituximab of these patients had influenza A virus subtype H1N1 infection achieved CR. (swine flu) and had to be followed in the intensive care unit. Infections Overall, 3 patients died due to infection, and one of them died because of a febrile neutropenic episode prior to treatment In 47 patients, 76 infectious episodes were noted during the initiation. In the remaining 2 cases, infections occurred during/ entire follow-up period (Table 3). Bacterial infections were the after treatment; IPA was the reason for death in one patient leading cause, and 64 bacterial infection episodes were observed. receiving first-line INF-α and the other patient died due to Of these 65 episodes, 14 were observed after diagnosis prior to sepsis following frontline 2-CdA administration. The distribution the initiation of any anti-HCL treatment, whereas 50 episodes of the infections and outcomes are shown in Table 3. were noted during treatment (Table 3). The infections were diagnosed by means of cultures, radiological imaging techniques, Survival and tissue biopsies as indicated. There were 18 patients who During the follow-up, 10 patients (12%) died (7 due to refractory required hospitalization (mostly due to neutropenic fever), and disease and/or infections, 3 due to AMI and sudden cardiac in 17 cases infections occurred within 30 days after completion death) and 2 patients were lost to follow-up. PFS and OS rates of treatment (all patients received 2-CdA). for the entire cohort after a median follow-up of 57 months There were 7 infection episodes caused by Mycobacterium were 62% (Figure 3A) and 83% (Figure 3B), respectively. With tuberculosis in 6 patients (5 pulmonary cases, 2 disseminated). regard to the first-line treatment, the PFS rate was significantly In 2 patients tuberculosis was diagnosed synchronously with higher for patients who received 2-CdA than those for patients HCL, and 5 episodes occurred during/after anti-HCL treatment. who were treated with INF-α and splenectomy (p=0.01 and In patients for whom tuberculosis was diagnosed prior to p<0.0001, respectively). However, PFS did not statistically differ treatment initiation, one had pulmonary tuberculosis and he between patients who were treated with INF-α and those who experienced disseminated disease 3 months after completing underwent splenectomy (p=0.213) (Figure 4A). There was no 2-CdA. The other patient had disseminated tuberculosis at statistically significant OS difference between these 3 treatment diagnosis, which was diagnosed via splenectomy. That patient modalities, although survival rates achieved with first-line then received INF-α due to relapse without any recurrence 2-CdA and INF-α seemed to be superior to those achieved with of tuberculosis. None of the patients with tuberculosis had splenectomy (Figure 4B). Figure 3. The progression-free survival (A) and overall survival (B) of the entire cohort. 2-CdA: Cladribine, INF-α: interferon-alpha. 295 Öngören Ş, et al: First-Line Treatment in Patients with HCL Turk J Hematol 2017;34:291-299 Table 3. The distribution of infections among the patient cohort. Type of infection Number of Timing of infection, n Type of treatment* Outcome of events, n infection (resolved/ death), n Prior to During/after treatment treatment initiation Viral (n=10) Flu 6 5 1 2-CdA (n=1) Herpes labialis 2 0 2 2-CdA (n=1) HBV 1 0 1 IFN (n=1) 10/0 HCV 1 0 1 2-CdA (n=1) IFN (n=1) [SPL, n=1] Bacterial (n=64) Pneumonia 13 7 6 2-CdA (n=4) [IFN, n=1] 13/0 IFN (n=2) [SPL, n=2] Tuberculosis 7 2 5 IFN (n=2) [SPL, n=1] 7/0 2-CdA (n=2) RTX (n=1) Febrile neutropenia 21 3 18 2-CdA (n=15) [IFN, n=3; RTX, n=1] 20/1 IFN (n=2) [SPL, n=1] RTX (n=1) Soft tissue infection 6 1 5 2-CdA (n=1) [RTX, n=1] 6/0 IFN (n=4) [SPL, n=2] Dental infection 3 0 3 IFN (n=1) [SPL, n=1] 3/0 2-CdA (n=2) [IFN, n=1] Paronychia 2 0 2 IFN (n=2) [SPL, n=1] 2/0 Sepsis 4 0 4 2-CdA (n=3) [IFN, n=1] 3/1 (2-CdA) IFN (n=1) [SPL, n=1] Conjunctivitis 2 1 1 2-CdA (n=1) 2/0 Septic arthritis 1 0 1 IFN (n=1) 1/0 Meningitis 1 0 1 IFN (n=1) 1/0 Urinary tract infection 3 0 3 2-CdA (n=2) [RTX, n=1] 3/0 RTX (n=1) Splenic abscess 1 0 1 IFN (n=1) 1/0 Fungal (n=2) Invasive pulmonary 2 0 2 IFN (n=1) 2/1 (IFN) aspergillosis 2-CdA (n=1) *In this column, the number of patients who received the defined most recent therapies is shown in parentheses, whereas the number of patients with a previous anti-HCL therapy is displayed in square brackets. 2-CdA: Cladribine, HBV: hepatitis B virus, HCV: hepatitis C virus, INF-α: interferon-alpha, SPL: splenectomy, HCL: hairy cell leukemia. occurs more frequently in males, and the median age of diagnosis Discussion is 52 years [14]. Our patient cohort showed characteristics that In this study we retrospectively evaluated the demographic were similar to the previously reported literature with a median features of patients with HCL and assessed the efficacy and age of 49 years and a male/female ratio of approximately 7:1. tolerability of the main first-line treatments together with the In our cohort, we identified peripheral and/or visceral subsequent therapy options and outcomes. We also identified the infections associated with the course of the disease. HCL lymphadenopathy in 27 patients (38%). In the most recent 296 Turk J Hematol 2017;34:291-299 Öngören Ş, et al: First-Line Treatment in Patients with HCL consensus guidelines for the diagnosis/management of patients With the upfront-usage of 2-CdA more responses have been with classic HCL, performing imaging studies for the detection of, reported to be higher and durable. In line with the literature, e.g., lymphadenopathy was optional [15]. It was recommended we only noted 16% R/R disease and a median treatment-free that these procedures be reserved for patients in a clinical trial or period of 23 months in our patients treated upfront with 2-CdA. those with associated symptoms referable to these systems [15]. We This was quite similar to what was reported by Saven et al. [17], did not routinely perform imaging studies for all of our patients, demonstrating a relapse rate of 26% after a median follow-up of but rather only for patients with signs/symptoms for which 29 months. However, with longer follow-up, relapse rates tended ultrasonography and/or computerized tomography scanning were to rise to 40% among patients who received 2-CdA upfront [18]. indicated. Furthermore, patients with HCL may develop infections Twenty-seven patients of our cohort (41%) had to be given (e.g., tuberculosis) or secondary primary tumors [16], where lymphadenopathy could be observed in the course of the disease. a second-line treatment for R/R disease after a median TTNT Most probably, in some of the patients, these enlarged lymph nodes of approximately 1 year. This was consistent with the findings are reactive or are due to other conditions, including infections. of Zinzani et al. [19], who found that nearly 44% of patients relapsed after a median of 2.7 years. In our cohort the median After the introduction of the purine analogues, the treatment TTNT was shorter than that observed in the cohort of Zinzani et algorithm of HCL evolved greatly [5]. Before that, splenectomy al. [19], and most probably the reason for this was the higher and IFN-α were the mainstays of the treatment [3,4]. The percentage of upfront purine analogue usage (85/121, 70%) management of HCL in Turkey also changed from the first among their patients than ours (31/66, 47%). As expected, years of the 2000s onwards with the availability of 2-CdA in patients receiving first-line 2-CdA had significantly lower the country, and prior to that time, patients with HCL were relapse rates than those treated with INF-α and splenectomy. receiving mainly INF-α and splenectomy upfront. Thereafter, Second-line 2-CdA treatment in our cohort of patients resulted 2-CdA became the standard choice of treatment for most in excellent response rates (ORR=100%). Relapse was observed patients with HCL. Earlier data indicate that patients who in one patient only, who also received second-line 2-CdA. Re- were treated with first-line splenectomy were usually younger treating relapsed patients with an additional course of purine than patients receiving IFN-α. Both splenectomy and IFN-α analogues is a reasonable option. Zinzani et al. [19] recommended have been associated with favorable clinical and hematologic repeating the same treatment regimen with purine analogues responses. However, the median survival with these treatment in relapse settings, although changing to a different purine modalities was approximately 4 years [3,4]. These earlier findings analogue might yield a better result. Unfortunately, 2-CdA is the were confirmed by our results indicating high but not durable only approved and available purine analogue in Turkey, so we ORRs with first-line splenectomy and IFN-α. We observed relapse rates as high as 70% and 50% in patients treated with did not have the opportunity of using other purine analogues splenectomy and IFN-α, respectively. like pentostatin in patients who relapsed after 2-CdA. Figure 4. The progression-free survival (A) and overall survival (B) when patients were divided into 3 groups according to the first-line treatment. *2-CdA vs. INF-α; **2-CdA vs. splenectomy; ***INF-α vs. splenectomy. 2-CdA: Cladribine, INF-α: interferon-alpha. 297 Öngören Ş, et al: First-Line Treatment in Patients with HCL Turk J Hematol 2017;34:291-299 Although the PFS rate with 2-CdA was significantly higher than to purine analogues or incorporation of new target-oriented those with INF-α and splenectomy, we found similar OS rates therapeutic agents such as BRAF, Bruton’s tyrosine kinase, or with all three upfront treatment modalities. Most probably one phosphoinositide 3-kinase inhibitors into treatment regimens of the reasons for this is the relatively short follow-up duration might help change the prognosis of the disease further, of our study. In addition to that, since most of the patients with especially for younger patients and for those who would poorly HCL may relapse during follow-up, sequentially re-challenging tolerate the current therapy options. the previous successful treatment(s) as well as the administration Ethics of alternative effective agents might have a positive impact on OS. In our cohort, switching to other potent therapies at relapse Ethics Committee Approval: Since the study has a retrospective could be another reasonable explanation for the comparable OS design, Ethics Committee approval is not needed. rates between these 3 first-line treatment groups. Informed Consent: Not applicable. A median follow-up duration of 57 months might not be enough to show OS benefit in patients with chronic leukemias such as Authorship Contributions HCL. After four lines of treatments with a median follow-up Surgical and Medical Practices:  Ş.Ö., A.E.E., S.B., T.E., A.S., of approximately 6 years, 10 patients died and 2 were lost to M.C.A., Z.B., Y.A., N.T., T.S.; Concept:  Ş.Ö., A.E.E.; Design:  Ş.Ö., follow-up, giving an OS rate of 83%, which was consistent with A.E.E.; Data Collection or Processing:  Ş.Ö., A.E.E., S.B.; Analysis the OS rate of 87% that was reported in the article by Zinzani or Interpretation:  Ş.Ö., A.E.E.; Literature Search:  Ş.Ö., A.E.E.; et al. [19]. Writing: Ş.Ö., A.E.E. One of the most important clinical problems in patients Conflict of Interest: The authors of this paper have no conflicts with HCL is the development of severe and sometimes life- of interest, including specific financial interests, relationships, threatening infections [20]. Gram-positive and gram-negative and/or affiliations relevant to the subject matter or materials organisms, Aspergillus, and other fungi are the most common included. pathogens [21], but tuberculosis [22] and herpes zoster [23] can be observed, as well. In our patient cohort, by far bacterial and References fungal infections were the most common, and 3 patients died 1. Bouroncle BA, Wiseman BK, Doan CA. Leukemic reticuloendotheliosis. Blood due to severe bacterial infection, sepsis, and IPA. We also had 6 1958;13:609-630. patients with 7 episodes of tuberculosis infection. Two patients 2. Schrek R, Donnelly WJ. ‘Hairy’ cells in blood in lymphoreticular neoplastic had tuberculosis and HCL at diagnosis, and 5 episodes occurred disease and ‘flagellated’ cells of normal lymph nodes. Blood 1966;27:199- during/after anti-HCL treatment. Tuberculosis is an important issue since it can lead to the misdiagnosis of patients for HCL 3. Berman E, Heller G, Kempin S, Gee T, Tran LL, Clarkson B. Incidence of response and long-term follow-up in patients with hairy cell leukemia relapse [22]. Thus, when a patient with HCL presents with fever, treated with recombinant interferon alfa-2a. Blood 1990;75:839-845. tuberculosis should always be kept in mind, especially where 4. Grever M, Kopecky K, Foucar MK, Head D, Bennett JM, Hutchison RE, tuberculosis is endemic. We had 2 patients with herpes labialis Corbett WE, Cassileth PA, Habermann T, Golomb H. Randomized comparison and 1 patient with influenza A virus subtype H1N1 infection, of pentostatin versus interferon alfa-2a in previously untreated patients with hairy cell leukemia: an intergroup study. J Clin Oncol 1995;13:974-982. which has also been documented in earlier reports on patients 5. Piro LD, Carrera CJ, Carson DA, Beutler E. Lasting remissions in hairy-cell with HCL [24]. leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med 1990;322:1117-1121. Conclusion 6. Dores GM, Matsuno RK, Weisenburger DD, Rosenberg PS, Anderson WF. Hairy cell leukaemia: a heterogeneous disease? Br J Haematol 2008;142:45-51. In conclusion, with the introduction of the purine analogues, 7. Zinzani PL, Ascani S, Piccaluga PP, Bendandi M, Pileri S, Tura S. Efficacy of the treatment of HCL has been greatly changed. Among our rituximab in hairy cell leukemia treatment. J Clin Oncol 2000;18:3875-3877. patient cohort, although ORRs were comparable for first-line 8. Nieva J, Bethel K, Saven A. Phase 2 study of rituximab in the treatment of 2-CdA, INF-α, and splenectomy, patients with frontline 2-CdA cladribine-failed patients with hairy cell leukemia. Blood 2003;102:810-813. had superior ORRs with more durable responses with a higher 9. Kreitman RJ, Wilson WH, Bergeron K, Raggio M, Stetler-Stevenson M, PFS rate than splenectomy and INF-α cases. The OS rate of FitzGerald DJ, Pastan I. Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N Engl J Med the entire cohort was consistent with the current literature. 2001;345:241-247. Infections including tuberculosis were a major problem, which 10. Tiacci E, Schiavoni G, Martelli MP, Boveri E, Pacini R, Tabarrini A, Zibellini S, caused morbidity and mortality. Santi A, Pettirossi V, Fortini E, Ascani S, Arcaini L, Inghirami G, Paulli M, Falini B. Constant activation of the RAF-MEK-ERK pathway as a diagnostic and Although purine analogues improved the CR rates and PFS, therapeutic target in hairy cell leukemia. Haematologica 2013;98:635-639. there is still much progress to be made with regard to OS and 11. Tiacci E, Park JH, De Carolis L, Chung SS, Broccoli A, Scott S, Zaja F, Devlin S, R/R disease. In that sense, the addition of monoclonal antibodies Pulsoni A, Chung YR, Cimminiello M, Kim E, Rossi D, Stone RM, Motta G, 298 Turk J Hematol 2017;34:291-299 Öngören Ş, et al: First-Line Treatment in Patients with HCL Saven A, Varettoni M, Altman JK, Anastasia A, Grever MR, Ambrosetti A, Rai lymph node: a diagnostic challenge and a rare coincidence. Case Rep Oncol KR, Fraticelli V, Lacouture ME, Carella AM, Levine RL, Leoni P, Rambaldi A, 2011;4:439-444. Falzetti F, Ascani S, Capponi M, Martelli MP, Park CY, Pileri SA, Rosen N, Foà 17. Saven A, Burian C, Koziol JA, Piro LD. Long-term follow-up of patients with R, Berger MF, Zinzani PL, Abdel-Wahab O, Falini B, Tallman MS. Targeting hairy cell leukemia after cladribine treatment. Blood 1998;92:1918-1926. mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med 18. Grever MR, Zinzani PL. Long-term follow-up studies in hairy cell leukemia. 2015;373:1733-1747. Leuk Lymphoma 2009;50(Suppl 1):23-26. 12. [No authors listed.] Consensus resolution: proposed criteria for evaluation 19. Zinzani PL, Pellegrini C, Stefoni V, Derenzini E, Gandolfi L, Broccoli A, of response to treatment in hairy cell leukemia. Leukemia 1987;1:405. Argnani L, Quirini F, Pileri S, Baccarani M. Hairy cell leukemia: evaluation of the long-term outcome in 121 patients. Cancer 2010;116:4788-4792. 13. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481. 20. Kraut E. Infectious complications in hairy cell leukemia. Leuk Lymphoma 2011;52(Suppl 2):50-52. 14. Cannon T, Mobarek D, Wegge J, Tabbara IA. Hairy cell leukemia: current 21. Golomb HM, Hadad LJ. Infectious complications in 127 patients with hairy concepts. Cancer Invest 2008;26:860-865. cell leukemia. Am J Hematol 1984;16:393-401. 15. Grever MR, Abdel-Wahab O, Andritsos LA, Banerji V, Barrientos J, Blachly 22. Gogia A, Raina V, Gupta R. Disseminated tuberculosis mimicking relapse in JS, Call TG, Catovsky D, Dearden C, Demeter J, Else M, Forconi F, Gozzetti hairy cell leukemia. Indian J Cancer 2013;50:321. A, Ho AD, Johnston JB, Jones J, Juliusson G, Kraut E, Kreitman RJ, Larratt L, Lauria F, Lozanski G, Montserrat E, Parikh SA, Park JH, Polliack A, Quest 23. Cheson BD, Sorensen JM, Vena DA, Montello MJ, Barrett JA, Damasio E, GR, Rai KR, Ravandi F, Robak T, Saven A, Seymour JF, Tadmor T, Tallman MS, Tallman M, Annino L, Connors J, Coiffier B, Lauria F. Treatment of hairy Tam C, Tiacci E, Troussard X, Zent CS, Zenz T, Zinzani PL, Falini B. Consensus cell leukemia with 2-chlorodeoxyadenosine via the Group C protocol guidelines for the diagnosis and management of patients with classic hairy mechanism of the National Cancer Institute: a report of 979 patients. J Clin cell leukemia. Blood 2017;129:553-560. Oncol 1998;16:3007-3015. 16. Aydin SO, Eskazan AE, Aki H, Ozguroglu M, Baslar Z, Soysal T. Synchronous 24. Nicolini A, Perazzo A. Influenza A H1N1 pneumonia in a patient with hairy- detection of hairy cell leukemia and HIV-negative Kaposi’s sarcoma of the cell leukemia. Monaldi Arch Chest Dis 2010;73:92-94. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Turkish Journal of Hematology Pubmed Central

Retrospective Evaluation of Hairy Cell Leukemia Patients Treated with Three Different First-Line Treatment Modalities in the Last Two Decades: A Single-Center Experience

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Pubmed Central
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© Turkish Journal of Hematology, Published by Galenos Publishing.
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1300-7777
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1308-5263
DOI
10.4274/tjh.2016.0443
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Abstract

Öz Objective: In this study, we retrospectively analyzed the clinical Amaç: Bu çalışmada, geriye dönük olarak 71 tüylü hücreli lösemi (SHL) outcome, treatment responses, infectious complications, and survival olgusunu klinik sonuçlar, tedavi yanıtları, enfeksiyon komplikasyonları rates of 71 hairy cell leukemia (HCL) cases. ve sağkalım oranları açısından analiz ettik. Materials and Methods: Sixty-seven patients received a first-line Gereç ve Yöntemler: Altmış yedi hasta birinci basamak tedavi almıştı treatment and 2-chlorodeoxyadenosine (cladribine-2-CdA) was ve 2-klorodeoksiadenozin (kladribin-2-CdA) 31 olguya uygulanmış, 19 administered in 31 cases, 19 patients received interferon-alpha hasta interferon-alfa (INF-α) almış, splenektomi 16 olguda uygulanmış (INF-α), splenectomy was performed in 16 cases, and rituximab was ve rituksimab ise bir hastada kullanılmıştı. used in one. Bulgular: En yüksek toplam yanıt oranı (TYO) birinci basamak 2-CdA Results: Although the highest overall response rate (ORR) was alan hastalarda görülmüş olsa da, TYO’lar 2-CdA, INF-α ve splenektomi observed in patients receiving 2-CdA upfront, ORRs were comparable alt gruplarında benzerdi. Nüks oranları birinci basamak 2-CdA alan in the 2-CdA, INF-α, and splenectomy subgroups. Relapse rates were hastalarda anlamlı olarak daha azdı. Progresyonsuz sağkalım (PS) oranı significantly lower in patients who received first-line 2-CdA. The 2-CdA alanlarda INF-α ve splenektomi hastalarına göre anlamlı olarak progression-free survival (PFS) rate with 2-CdA was significantly daha yüksek olmakla birlikte, her üç birinci basamak tedavi yaklaşımı higher than in patients with INF-α and splenectomy, but we found ile toplam sağkalım (TS) oranları benzer olarak bulundu. Tüberkülozun similar overall survival rates with all three upfront treatment da dahil olduğu enfeksiyonlar önemli bir problemdi. modalities. Infections including tuberculosis were a major problem. Sonuç: Her ne kadar pürin analogları TYO ve PS’yi iyileştirmiş olsa da, Conclusion: Although purine analogues have improved the ORRs and SHL hastalarında TS ve nüks/dirençli hastalık açısından daha yapılması PFS, there is still much progress to make with regard to overall survival gereken çok şey vardır. and relapsed/refractory disease in patients with HCL. Anahtar Sözcükler: Kladribin, Tüylü hücreli lösemi, İnterferon, Keywords: Cladribine, Hairy cell leukemia, Interferon, Splenectomy Splenektomi Most patients eventually require therapy owing to worsening Introduction cytopenias, frequent and life-threatening infections, and/ Hairy cell leukemia (HCL) is a rare mature B-cell neoplasm or symptomatic splenomegaly. Several treatment modalities, characterized by the accumulation of atypical lymphocytes including splenectomy and immunotherapy with interferon- with prominent cytoplasmic projections in the bone marrow and spleen, resulting in pancytopenia and splenomegaly [1,2]. alpha (INF-α), were used with various clinical and hematologic ©Copyright 2017 by Turkish Society of Hematology Turkish Journal of Hematology, Published by Galenos Publishing House Address for Correspondence/Yazışma Adresi: Şeniz ÖNGÖREN, M.D., Received/Geliş tarihi: November 10, 2016 İstanbul University Cerrahpaşa Faculty of Medicine, Department of Hematology, İstanbul, Turkey Accepted/Kabul tarihi: July 26, 2017 Phone : +90 532 334 16 64 E-mail : senizongoren@hotmail.com ORCID-ID: orcid.org/0000-0002-2809-5510 291 Öngören Ş, et al: First-Line Treatment in Patients with HCL Turk J Hematol 2017;34:291-299 responses until the introduction of the purine nucleoside disappearance of hepatosplenomegaly and cytopenias. analogues 2-chlorodeoxyadenosine (cladribine, 2-CdA) and Normalization of peripheral blood counts together with an at least 50% reduction in the size of organomegaly and the volume 2′-deoxycoformycin (pentostatin) [3,4,5]. Purine analogues of bone marrow HCs, plus <5% circulating HCs, was designated have resulted in higher complete response (CR) rates and as partial response (PR). Presence of CR or PR was defined as durable remissions, and they have become the treatment of overall response (OR), and any response other than a CR or PR choice in most cases [6]. Monoclonal antibodies (i.e. rituximab) was considered as no response. During response evaluation, a and immunotoxins are currently recommended for relapsed/ bone marrow biopsy was performed 3 months after finishing refractory (R/R) cases [7,8,9]. Also among the target-oriented 2-CdA treatment. Furthermore, relapse after CR was defined as therapeutic options, the BRAF inhibitor vemurafenib can be the reappearance of HCs in the peripheral blood or bone marrow, used in patients with R/R HCL [10,11]. development of cytopenias, and/or splenomegaly on physical In this study, we retrospectively analyzed the clinical outcome, examination. Relapse after PR indicated a >50% increase of treatment responses, infectious complications, and survival rates residual disease. of HCL patients treated in our institution with three treatment Overall survival (OS) denotes the time from the first treatment modalities (splenectomy, INF-α, and 2-CdA) as first-line therapy until the time of death or last follow-up. The duration of between 1991 and 2014. progression-free survival (PFS) was calculated from the onset of any first-line treatment until the date of progression. Time to Materials and Methods next treatment (TTNT) was calculated as the time from the end Patients of the previous treatment to the institution of the next therapy. A total of 71 patients with HCL, who were diagnosed and Statistical Analysis followed in our clinic over the past 20 years, were included in this Student’s t-test was used for the comparison of the quantitative study. Diagnosis of HCL was established by morphological, flow- variables. Qualitative variables between groups were compared cytometric, and immunohistochemical analysis of peripheral using the chi-square test. The Kaplan-Meier method was used blood, bone marrow, and/or spleen specimens. Information on for survival analysis [13]. Survival rates were compared by the patients’ characteristics, presenting signs and symptoms, using the log-rank test. All tests were two-sided, and p<0.05 treatment modalities and outcomes, and infections were was considered as statistically significant. All analyses were retrospectively taken from the patients’ files. While defining the performed with SPSS 13.0 for Windows (SPSS Inc., Chicago, IL, patient cohort, we excluded cases with variant HCL. USA). Treatment Modalities Results Patients were divided into 3 subgroups according to the first-line treatments (i.e. splenectomy, INF-α, and 2-CdA) Sixty-two patients (87%) were male and the median age was 49 that they had received. Splenectomy was performed either years (range: 31-76 years). There were 53 patients (75%) with laparoscopically or via open surgery. 2-CdA was given either splenomegaly, and the numbers of patients with hepatomegaly by continuous intravenous infusion at a dose of 0.1 mg/kg/ and lymphadenopathy were 32 (45%) and 27 (38%), respectively. day over 7 consecutive days, or by 2-h intravenous infusion The demographic features of the entire cohort including median at a dose of 0.1 mg/kg once a week for 7 consecutive weeks, leukocyte and platelet counts and hemoglobin levels at diagnosis depending on whether the patients received it as an inpatient or are displayed in Table 1. The median duration of follow-up was outpatient treatment, respectively. While on 2-CdA, the patients 57 months (range: 1-217 months). At diagnosis, all patients were given cotrimoxazole prophylaxis against Pneumocystis had bone marrow biopsy, and flow cytometric evaluation was jirovecii pneumonia. INF-α was administered subcutaneously at performed for 47 patients (66%) from peripheral blood and/ a starting dose of 3 MU 3 times a week and maintained with or bone marrow. At diagnosis, hematoxylin and eosin staining, subsequent toxicity-based dose adjustments. Rituximab was reticulin staining, tartrate-resistant acid phosphatase staining, administered at the conventional dose of 375 mg/m weekly for and immunohistochemistry for CD20 and annexin A1 were 4 consecutive weeks, as suggested before [7]. performed from the bone marrow aspiration and trephine biopsy. Definition of Response and Survival Treatments and Outcomes Among the patient cohort, there were 4 patients who did not Response to treatment was assessed using the criteria described in the consensus resolution of 1987 [12]. Accordingly, CR was receive treatment. Two of them were lost to follow-up, one defined as the morphological absence of hairy cells (HCs) patient died due to severe infection, and one had an acute in the blood and the bone marrow in addition to complete myocardial infarction (AMI) and died before any treatment was 292 Turk J Hematol 2017;34:291-299 Öngören Ş, et al: First-Line Treatment in Patients with HCL initiated (Figure 1). were 97%, 84%, and 81%, respectively, and although the ORR of 2-CdA treatment was superior to those of the other 2 groups, First-Line Treatment the differences were not significant (Figure 2). During the first- line treatment, 2 patients (one on 2-CdA and one on INF-α) died Sixty-seven (94%) patients received a first-line treatment. due to infection (Figure 1). No postoperative complications were 2-CdA was administered for 31 patients (46%), 19 patients observed in patients with splenectomy. (28%) received INF-α, splenectomy was performed in 16 cases (24%), and rituximab was used in one case (2%) (Figure 1). Five of the 31 patients who received 2-CdA as the first-line Although patients in the splenectomy arm were younger than therapy required a second-line treatment after a median TTNT those in the other 2 arms, the differences were not statistically of 23 months (range: 3-58 months) (Table 2). There were 10 significant (Table 2). The 3 treatment subgroups were equally patients in the first-line INF-α subgroup who progressed and balanced regarding sex distribution, median hemoglobin levels, needed a second-line treatment following a median TTNT of 21 and leukocyte and platelet counts (Table 2). There were 30, 16, months (range: 1-96 months). Eleven of the 16 patients who and 13 patients who achieved OR after the first-line treatment underwent first-line splenectomy received a second-line therapy due to relapsed disease at a median TTNT of 5 months (range: with 2-CdA, INF-α, and splenectomy, respectively (Figure 1). The 2-73 months). Relapse rates were significantly lower in patients OR rates (ORRs) in the 2-CdA, INF-α, and splenectomy subgroups who received first-line 2-CdA than those who were treated with INF-α or splenectomy (p=0.007 and p<0.0001, respectively). However, this was not significantly different when the INF-α and splenectomy subgroups were compared (p=0.339) (Table 2). Although the patients with first-line splenectomy had a shorter median TTNT than those with 2-CdA and INF-α, the difference did not reach statistical significance (Table 2). The only patient who received rituximab as frontline treatment remained refractory to that therapy, and she needed further treatment. Second-Line Treatment With a median TTNT of 13 months (range: 1-96 months), 27 patients required a second-line treatment due to R/R disease. Figure 1. The distribution of first-line treatment modalities and Twelve patients received INF-α, 11 patients were treated with outcomes. 2-CdA, 3 patients underwent splenectomy, and one received 2-CdA: Cladribine, HCL: hairy cell leukemia, INF-α: interferon-alpha, RTX: rituximab, SPL: splenectomy, ORR: overall response rate, NRR: non-response rate. fludarabine. *See text for details. Eight and 2 of the 12 patients who received second-line INF-α had been initially treated with splenectomy and 2-CdA, Table 1. The baseline characteristics of the patients. Parameter  Entire cohort (n=71)  Sex - male/female, n (%)  62 (87)/9 (13) Median age, years (min-max)  49 (31-76) Median leukocyte count, x10 /L (min-max)  3.0 (0.5-9.4) Median hemoglobin level, g/dL (min-max) 10 (4-17) Median platelet count, x10 /L (min-max)  51.5 (21-124) Splenomegaly - yes/no, n (%) 53 (75)/18 (25) Mean spleen size, cm (min-max)* 11.4 (2-26) Hepatomegaly - yes/no, n (%)  32 (45)/39 (55) Lymphadenopathy - yes/no, n (%)  27 (38)/44 (62) Figure 2. Response rates according to the different first-line treatment modalities. Median follow-up duration, 57 (1-217) *2-CdA vs. INF-α; **2-CdA vs. splenectomy; ***INF-α vs. splenectomy. months (min-max)  *Spleen size was measured by physical examination and stated as the distance from ORR: Overall response rate, NRR: non-response rate, 2-CdA: cladribine, INF-α: the left costal margin in cm. interferon-alpha. 293 Öngören Ş, et al: First-Line Treatment in Patients with HCL Turk J Hematol 2017;34:291-299 respectively. In the remaining 2 patients the previous treatment Third-Line Treatment was also INF-α. The ORR was 100% in patients who received There were 6 patients who needed third-line treatment. INF-α, second-line INF-α, with only 3 patients requiring a third-line 2-CdA, and rituximab were used for 3, 2, and one of them, treatment due to relapsed disease. respectively, following a median TTNT of 36 months (range: 8-63 months). Among patients receiving third-line INF-α, one In patients who had 2-CdA as a second-line treatment, 7 had achieved and maintained CR throughout the entire follow-up. received INF-α as the first-line therapy, and 2 had splenectomy. The other 2 remained refractory to INF-α treatment; one died, The other 2 had been treated with rituximab and 2-CdA previously. and the other patient proceeded to fourth-line treatment. One All the patients responded to second-line 2-CdA (the ORR was of the 2 patients who received 2-CdA as a third-line treatment 100%), and only one relapsed after a follow-up of 48 months. achieved and maintained CR and the other patient died due to refractory disease. Splenectomy was performed in 3 patients as a second-line treatment. All of them initially responded to splenectomy; The patient who received third-line weekly rituximab could not th however, 2 needed further treatment due to relapsed disease. complete the 4 week of treatment due to an allergic reaction, rd The patient who received fludarabine as a second-line therapy which had happened following the 3 dose of the drug, and had achieved PR but was then lost to follow-up after 9 months. to proceed to fourth-line therapy. Table 2. Patient characteristics and treatment outcomes in patients with 3 first-line treatment options. First-Line Treatment (n=67) Parameter 2-CdA INF-α Splenectomy p value (n=31) (n=19) (n=16) Sex - male/female, n (%) 27 (87)/4 (13) 18 (95)/1 (5) 14 (88)/2 (12) 0.387* 0.969** 0.453*** Median age, years (min-max) 52 (33-75) 50 (33-76) 47.5 (31-64) 0.564* 0.094** 0.061*** Median leukocyte count, x10 /L (min-max) 3.1 (1.6-7.2) 3.0 (0.5-9.4) 3.4 (0.5-9.1) 0.601* 0.510** 0.392*** Median hemoglobin level, g/dL (min-max) 11 (5-17) 10 (4-14) 9 (5-15) 0.098* 0.053** 0.721*** Median platelet count, x10 /L (min-max) 62 (22-108) 42.5 (21-124) 56 (29-81) 0.624* 0.552** 0.888*** Patients needing further treatment(s) due to R/R disease, n (%) 5 (16) 10 (53) 11 (69) 0.007* <0.0001** 0.339*** Median TTNT, months (min-max) 23 (3-58) 21 (1-96) 5 (2-73) 0.902* 0.370** 0.190*** Median follow-up, months (min-max) 53 (5-213) 57 (2-154) 83 (15-217) 0.739* 0.120** 0.230*** One patient received rituximab as a first-line treatment, *2-CdA vs. INF- α; **2-CdA vs. splenectomy; ***INF-α vs. splenectomy. R/R: Relapsed/refractory, TTNT: time to next treatment, 2-CdA: cladribine. 294 Turk J Hematol 2017;34:291-299 Öngören Ş, et al: First-Line Treatment in Patients with HCL Fourth-Line Treatment drug-resistant disease, and none of them had any known comorbidities including diabetes. There were also 2 patients There were only 2 patients who received a fourth-line with invasive pulmonary aspergillosis (IPA). treatment. One of them was treated with INF-α and the other with rituximab. The patient who received INF-α died due to Six of the 10 episodes of viral infections were related to flu. One refractory disease, and the patient who was given rituximab of these patients had influenza A virus subtype H1N1 infection achieved CR. (swine flu) and had to be followed in the intensive care unit. Infections Overall, 3 patients died due to infection, and one of them died because of a febrile neutropenic episode prior to treatment In 47 patients, 76 infectious episodes were noted during the initiation. In the remaining 2 cases, infections occurred during/ entire follow-up period (Table 3). Bacterial infections were the after treatment; IPA was the reason for death in one patient leading cause, and 64 bacterial infection episodes were observed. receiving first-line INF-α and the other patient died due to Of these 65 episodes, 14 were observed after diagnosis prior to sepsis following frontline 2-CdA administration. The distribution the initiation of any anti-HCL treatment, whereas 50 episodes of the infections and outcomes are shown in Table 3. were noted during treatment (Table 3). The infections were diagnosed by means of cultures, radiological imaging techniques, Survival and tissue biopsies as indicated. There were 18 patients who During the follow-up, 10 patients (12%) died (7 due to refractory required hospitalization (mostly due to neutropenic fever), and disease and/or infections, 3 due to AMI and sudden cardiac in 17 cases infections occurred within 30 days after completion death) and 2 patients were lost to follow-up. PFS and OS rates of treatment (all patients received 2-CdA). for the entire cohort after a median follow-up of 57 months There were 7 infection episodes caused by Mycobacterium were 62% (Figure 3A) and 83% (Figure 3B), respectively. With tuberculosis in 6 patients (5 pulmonary cases, 2 disseminated). regard to the first-line treatment, the PFS rate was significantly In 2 patients tuberculosis was diagnosed synchronously with higher for patients who received 2-CdA than those for patients HCL, and 5 episodes occurred during/after anti-HCL treatment. who were treated with INF-α and splenectomy (p=0.01 and In patients for whom tuberculosis was diagnosed prior to p<0.0001, respectively). However, PFS did not statistically differ treatment initiation, one had pulmonary tuberculosis and he between patients who were treated with INF-α and those who experienced disseminated disease 3 months after completing underwent splenectomy (p=0.213) (Figure 4A). There was no 2-CdA. The other patient had disseminated tuberculosis at statistically significant OS difference between these 3 treatment diagnosis, which was diagnosed via splenectomy. That patient modalities, although survival rates achieved with first-line then received INF-α due to relapse without any recurrence 2-CdA and INF-α seemed to be superior to those achieved with of tuberculosis. None of the patients with tuberculosis had splenectomy (Figure 4B). Figure 3. The progression-free survival (A) and overall survival (B) of the entire cohort. 2-CdA: Cladribine, INF-α: interferon-alpha. 295 Öngören Ş, et al: First-Line Treatment in Patients with HCL Turk J Hematol 2017;34:291-299 Table 3. The distribution of infections among the patient cohort. Type of infection Number of Timing of infection, n Type of treatment* Outcome of events, n infection (resolved/ death), n Prior to During/after treatment treatment initiation Viral (n=10) Flu 6 5 1 2-CdA (n=1) Herpes labialis 2 0 2 2-CdA (n=1) HBV 1 0 1 IFN (n=1) 10/0 HCV 1 0 1 2-CdA (n=1) IFN (n=1) [SPL, n=1] Bacterial (n=64) Pneumonia 13 7 6 2-CdA (n=4) [IFN, n=1] 13/0 IFN (n=2) [SPL, n=2] Tuberculosis 7 2 5 IFN (n=2) [SPL, n=1] 7/0 2-CdA (n=2) RTX (n=1) Febrile neutropenia 21 3 18 2-CdA (n=15) [IFN, n=3; RTX, n=1] 20/1 IFN (n=2) [SPL, n=1] RTX (n=1) Soft tissue infection 6 1 5 2-CdA (n=1) [RTX, n=1] 6/0 IFN (n=4) [SPL, n=2] Dental infection 3 0 3 IFN (n=1) [SPL, n=1] 3/0 2-CdA (n=2) [IFN, n=1] Paronychia 2 0 2 IFN (n=2) [SPL, n=1] 2/0 Sepsis 4 0 4 2-CdA (n=3) [IFN, n=1] 3/1 (2-CdA) IFN (n=1) [SPL, n=1] Conjunctivitis 2 1 1 2-CdA (n=1) 2/0 Septic arthritis 1 0 1 IFN (n=1) 1/0 Meningitis 1 0 1 IFN (n=1) 1/0 Urinary tract infection 3 0 3 2-CdA (n=2) [RTX, n=1] 3/0 RTX (n=1) Splenic abscess 1 0 1 IFN (n=1) 1/0 Fungal (n=2) Invasive pulmonary 2 0 2 IFN (n=1) 2/1 (IFN) aspergillosis 2-CdA (n=1) *In this column, the number of patients who received the defined most recent therapies is shown in parentheses, whereas the number of patients with a previous anti-HCL therapy is displayed in square brackets. 2-CdA: Cladribine, HBV: hepatitis B virus, HCV: hepatitis C virus, INF-α: interferon-alpha, SPL: splenectomy, HCL: hairy cell leukemia. occurs more frequently in males, and the median age of diagnosis Discussion is 52 years [14]. Our patient cohort showed characteristics that In this study we retrospectively evaluated the demographic were similar to the previously reported literature with a median features of patients with HCL and assessed the efficacy and age of 49 years and a male/female ratio of approximately 7:1. tolerability of the main first-line treatments together with the In our cohort, we identified peripheral and/or visceral subsequent therapy options and outcomes. We also identified the infections associated with the course of the disease. HCL lymphadenopathy in 27 patients (38%). In the most recent 296 Turk J Hematol 2017;34:291-299 Öngören Ş, et al: First-Line Treatment in Patients with HCL consensus guidelines for the diagnosis/management of patients With the upfront-usage of 2-CdA more responses have been with classic HCL, performing imaging studies for the detection of, reported to be higher and durable. In line with the literature, e.g., lymphadenopathy was optional [15]. It was recommended we only noted 16% R/R disease and a median treatment-free that these procedures be reserved for patients in a clinical trial or period of 23 months in our patients treated upfront with 2-CdA. those with associated symptoms referable to these systems [15]. We This was quite similar to what was reported by Saven et al. [17], did not routinely perform imaging studies for all of our patients, demonstrating a relapse rate of 26% after a median follow-up of but rather only for patients with signs/symptoms for which 29 months. However, with longer follow-up, relapse rates tended ultrasonography and/or computerized tomography scanning were to rise to 40% among patients who received 2-CdA upfront [18]. indicated. Furthermore, patients with HCL may develop infections Twenty-seven patients of our cohort (41%) had to be given (e.g., tuberculosis) or secondary primary tumors [16], where lymphadenopathy could be observed in the course of the disease. a second-line treatment for R/R disease after a median TTNT Most probably, in some of the patients, these enlarged lymph nodes of approximately 1 year. This was consistent with the findings are reactive or are due to other conditions, including infections. of Zinzani et al. [19], who found that nearly 44% of patients relapsed after a median of 2.7 years. In our cohort the median After the introduction of the purine analogues, the treatment TTNT was shorter than that observed in the cohort of Zinzani et algorithm of HCL evolved greatly [5]. Before that, splenectomy al. [19], and most probably the reason for this was the higher and IFN-α were the mainstays of the treatment [3,4]. The percentage of upfront purine analogue usage (85/121, 70%) management of HCL in Turkey also changed from the first among their patients than ours (31/66, 47%). As expected, years of the 2000s onwards with the availability of 2-CdA in patients receiving first-line 2-CdA had significantly lower the country, and prior to that time, patients with HCL were relapse rates than those treated with INF-α and splenectomy. receiving mainly INF-α and splenectomy upfront. Thereafter, Second-line 2-CdA treatment in our cohort of patients resulted 2-CdA became the standard choice of treatment for most in excellent response rates (ORR=100%). Relapse was observed patients with HCL. Earlier data indicate that patients who in one patient only, who also received second-line 2-CdA. Re- were treated with first-line splenectomy were usually younger treating relapsed patients with an additional course of purine than patients receiving IFN-α. Both splenectomy and IFN-α analogues is a reasonable option. Zinzani et al. [19] recommended have been associated with favorable clinical and hematologic repeating the same treatment regimen with purine analogues responses. However, the median survival with these treatment in relapse settings, although changing to a different purine modalities was approximately 4 years [3,4]. These earlier findings analogue might yield a better result. Unfortunately, 2-CdA is the were confirmed by our results indicating high but not durable only approved and available purine analogue in Turkey, so we ORRs with first-line splenectomy and IFN-α. We observed relapse rates as high as 70% and 50% in patients treated with did not have the opportunity of using other purine analogues splenectomy and IFN-α, respectively. like pentostatin in patients who relapsed after 2-CdA. Figure 4. The progression-free survival (A) and overall survival (B) when patients were divided into 3 groups according to the first-line treatment. *2-CdA vs. INF-α; **2-CdA vs. splenectomy; ***INF-α vs. splenectomy. 2-CdA: Cladribine, INF-α: interferon-alpha. 297 Öngören Ş, et al: First-Line Treatment in Patients with HCL Turk J Hematol 2017;34:291-299 Although the PFS rate with 2-CdA was significantly higher than to purine analogues or incorporation of new target-oriented those with INF-α and splenectomy, we found similar OS rates therapeutic agents such as BRAF, Bruton’s tyrosine kinase, or with all three upfront treatment modalities. Most probably one phosphoinositide 3-kinase inhibitors into treatment regimens of the reasons for this is the relatively short follow-up duration might help change the prognosis of the disease further, of our study. In addition to that, since most of the patients with especially for younger patients and for those who would poorly HCL may relapse during follow-up, sequentially re-challenging tolerate the current therapy options. the previous successful treatment(s) as well as the administration Ethics of alternative effective agents might have a positive impact on OS. In our cohort, switching to other potent therapies at relapse Ethics Committee Approval: Since the study has a retrospective could be another reasonable explanation for the comparable OS design, Ethics Committee approval is not needed. rates between these 3 first-line treatment groups. Informed Consent: Not applicable. A median follow-up duration of 57 months might not be enough to show OS benefit in patients with chronic leukemias such as Authorship Contributions HCL. After four lines of treatments with a median follow-up Surgical and Medical Practices:  Ş.Ö., A.E.E., S.B., T.E., A.S., of approximately 6 years, 10 patients died and 2 were lost to M.C.A., Z.B., Y.A., N.T., T.S.; Concept:  Ş.Ö., A.E.E.; Design:  Ş.Ö., follow-up, giving an OS rate of 83%, which was consistent with A.E.E.; Data Collection or Processing:  Ş.Ö., A.E.E., S.B.; Analysis the OS rate of 87% that was reported in the article by Zinzani or Interpretation:  Ş.Ö., A.E.E.; Literature Search:  Ş.Ö., A.E.E.; et al. [19]. Writing: Ş.Ö., A.E.E. One of the most important clinical problems in patients Conflict of Interest: The authors of this paper have no conflicts with HCL is the development of severe and sometimes life- of interest, including specific financial interests, relationships, threatening infections [20]. Gram-positive and gram-negative and/or affiliations relevant to the subject matter or materials organisms, Aspergillus, and other fungi are the most common included. pathogens [21], but tuberculosis [22] and herpes zoster [23] can be observed, as well. In our patient cohort, by far bacterial and References fungal infections were the most common, and 3 patients died 1. Bouroncle BA, Wiseman BK, Doan CA. Leukemic reticuloendotheliosis. Blood due to severe bacterial infection, sepsis, and IPA. We also had 6 1958;13:609-630. patients with 7 episodes of tuberculosis infection. Two patients 2. Schrek R, Donnelly WJ. ‘Hairy’ cells in blood in lymphoreticular neoplastic had tuberculosis and HCL at diagnosis, and 5 episodes occurred disease and ‘flagellated’ cells of normal lymph nodes. Blood 1966;27:199- during/after anti-HCL treatment. Tuberculosis is an important issue since it can lead to the misdiagnosis of patients for HCL 3. Berman E, Heller G, Kempin S, Gee T, Tran LL, Clarkson B. 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Journal

Turkish Journal of HematologyPubmed Central

Published: Dec 1, 2017

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