Long-Term Outcome with Pentostatin Treatment in Hairy Cell Leukemia Patients

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Leukemia (2003) 17, 45–51  2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu Long-term outcome with pentostatin treatment in hairy cell leukemia patients. A French retrospective study of 238 patients F Maloisel1, L Benboubker2, M Gardembas3, B Coifﬁer4, M Divine5, C Sebban6, M Blanc7, J-F Abgrall8, P Lederlin9, J-L Harousseau10, A-M Blaise11, B Grosbois12, P Morice13, C Ghandour14 and S Castaigne15

1De´partement d’He´matologie et d’Oncologie, HUS, Strasbourg, France; 2Service d’Oncologie Me´dicale et des Maladies du Sang, CHU, Tours, France; 3Service des Maladies du Sang, CHU, Angers, France; 4Service d’He´matologie, Clinique Centre Hospitalier Lyon Sud Pierre Benite, France; 5Service d’He´matologie Hopital Henri Mondor, Creteil, France; 6Service d’He´matologie Hopital Edouard Herriot, Lyon, France; 7Service de Me´decine A7, Centre Hospitalier, Chambe´ry, France; 8Service d’He´matologie-Oncologie-He´mostase, Hopital Augustin Morvan, Brest, France; 9Service de Me´decine A, CHU Brabois, Nancy, France; 10Service d’He´matologie, Clinique Hopital Hotel-Dieu, Nantes, France; 11De´partement de Me´decine Interne et d’He´matologie, Clinique Hopital Robert Debre´, Reims, France; 12Service de Me´decine G, CHRU Hopital Sud, Rennes, France; 13Service d’He´matologie et d’Oncologie Me´dicale, Hopital Yves Le Foll, St Brieuc, France; 14Cabinet d’He´matologie-Oncologie Polyclinique Sevigne´, Rennes, France; and 15Service d’He´matologie et d’Oncologie, CH de Versailles, France

With the introduction of new drugs such as alpha-interferon mately 4 years before systemiceffectivetherapy was intro- (IFN) and purine analogs, the management of hairy cell leuke- duced.2 Splenectomy was the first treatment modality to be mia (HCL) patients has changed. However, deoxycoformycin (DCF) produced higher complete remission rates than IFN. The regularly used in HCL and it was able to achieve a rapid per- current study was undertaken to provide long-term data on dur- ipheral hematologic reconstitution even in the presence of ation of overall survival (OS) and disease-free survival (DFS) severe cytopenia.3 Although splenectomy decreased cyto- and incidence of subsequent malignancies. We retrospectively penia, it had no effect on bone marrow infiltration, meaning analyzed the data of patients treated with DCF (4 mg/m2/day, that eventually another treatment was necessary. With the every 2 weeks) from 39 French centers. In 84 of 238 included introduction of new drugs, such as alpha-interferon (IFN), 2Ј patients, DCF was the first-line therapy. Pretreatment variables Ј influencing the achievement of complete remission, DFS, and deoxycoformycin (DCF), and 2 -chlorodeoxyadenosine OS were identified by multivariate analysis. Two hundred and (2CdA), the management of HCL patients changed. The last thirty-eight patients received a median of nine cycles (range, two were purine analogs that differ in their interaction with 1–19 cycles). A complete remission was obtained in 182 of 230 adenosine deaminase, the enzyme that plays a role in the evaluable patients (79%) and a partial response was obtained purine metabolism and which is present in high concen- in 38 patients, for an overall response rate of 95.6%. In the trations in lymphoid tissues.4 The proportion of patients multivariate analysis hemoglobin level less than 100 g/l and leukocytes less than 2 × 109/l were parameters adversely influ- obtaining a response with IFN ranged from 0% to 43% for encing complete remission achievement. With a median follow- complete remission (CR) and rose to 90% for partial response up of 63.5 months (range, 0.39–138.4 months), disease recur- (PR), but the majority of patients relapsed after stopping ther- rence was observed in 34 of 220 responding patients (15%). apy.5 A randomized study, with a cross-over design, compar- The estimated 5-years and 10-years DFS was 88.1% and 68.8%, ing DCF to IFN demonstrated that DCF produced a higher respectively. Hemoglobin level less than 100 g/l and leukocytes complete remission rate with more durable response, but × 9 less than 2 10 /l were the pre-treatment variables associated 6 with a shorter DFS. The estimated 5-year and 10-year OS were without differences in terms of survival. Since the first publi- 89.4% and 88.7%, respectively. Hemoglobin level less than 100 cation on DCF activity in HCL patients, numerous studies con- g/l, leukocytes less than 2 × 109/l, and adenopathy were signifi- firmed this observation.7–11 In the first clinical trials, patients cant factors of reduced survival. Hematologic toxicity was the were treated with higher doses but severe neurologicadverse main side-effect, followed by infection and emesis. During the events were noted and, secondarily, it was reported that lower period of follow-up, 18 patients developed second cancer, but doses (4 mg/m2) was less toxic with the same efficacy.7 the standardized incidence ratio was 0.95. Pentostatin is a highly effective regimen for hairy cell leukemia that produces Recently, the appearence of second malignancies after purine durable complete responses. Toxicity of DCF is acceptable. analogs was regarded as a potential problem and was Subsequent malignancies do not appear to be increased with observed in 10% of patients treated with DCF.2 pentostatin treatment. We report here a large cohort of patients with HCL treated Leukemia (2003) 17, 45–51. doi:10.1038/sj.leu.2402784 with DCF and a median follow-up of 63.5 months. Keywords: hairy cell leukemia; deoxycoformycin; long-term follow- up; secondary cancer Materials and methods

Introduction Patients, treatment schedule and criteria of response

Hairy cell leukemia (HCL) is a rare lymphoproliferative malig- Retrospectively, data of HCL patients from 39 French centers nancy first described in 1958 and referred to originally as leu- treated with DCF between March 1989 and December 1997 1 kemicreticuloendotheliosis. The natural history of this were analyzed. Data files were reviewed before inclusion in lymphoproliferative disorder varies. Studies on HCL from the present analysis and patients were required to have: (1) a 1958 to 1984 showed a median survival time of approxi- confirmed diagnosis of HCL on the basis of peripheral blood, bone marrow biopsy, and immunophenotype; (2) an active disease as manifested by progressive cytopenia (neutrophil Correspondence: F Maloisel, Department of Hematology and count less than 1 × 109/l, or hemoglobin level less than 100 Oncology, Hoˆpital Civil, 1 place de l’hoˆpital, 67091 Strasbourg, × 9 France; Fax: 33–388 115805; Email: Frederic.Maloisel@chru- g/l, or thrombocytopenia less than 100 10 /l), recurrent strasbourg.fr infections, or massive splenomegaly; (3) patients required Received 3 May 2002; accepted 22 August 2002 abdominal evaluation by CT scans; (4) an adequate renal and Pentostatin in hairy cell leukemia F Maloisel et al 46 liver function (creatinin less than 1.5 N and liver enzymes less mentioned above. The proportional hazard assumption was than 2.5 N); (5) patients could have been either untreated or validated on the most statistically significant covariates. have previously been treated with splenectomy, systemic To determine whether there was an excess of secondary chemotherapy, or both. primary tumors (occurring after the diagnosis of HCL), we DCF was given at a dose of 4 mg/m2 by intravenous bolus computed standardized incidence ratio calculated by injection every 2 weeks and was continued to the point of determining the ratio of the observed to expected number of maximal response or treatment failure. No maintenance ther- individuals with second malignancies. The expected number apy was given. Any recurrence of cytopenia after the fourth of individuals with secondary invasive malignancies course would postpone treatment until recuperation to near (excluding non-melanoma skin cancer) was determined using normal values. age, sex, and calendar-year-specific incidence rate extra- Established response criteria were used and are summarized polated from the main French cancer registries.14 as follows: CR was defined as (1) disappearence of any evi- Results presented here are based on data available as of 15 dence of HCL cell in blood and bone marrow; (2) achieve- March 2001. Statistical analysis was carried out by Biotrial, ment of hemoglobin level greater than 120 g/l, platelet count Rennes, France. greater than 100 × 109/l, and absolute neutrophil count (ANC) greater than 1.5 × 109/l; (3) normalization of spleen size if originally abnormal; and (4) resolution of adenopathy if orig- Results inally present. Patients who presented all peripheral blood CR criteria except the bone marrow control were considered as Patient’s characteristics unconfirmed CR (CRu). PR required all the following: (1) normal blood counts as stated above; (2) reduction of initial Table 1 shows the main clinical features at the start of treat- spleen size by more than 50%; (3) a 50% reduction or greater ment for the 238 patients included in the present study: 154 in the percentage of hairy cell infiltration in the bone marrow. (64.7%) patients had received prior treatment, including inter- Patients who did not fulfill the above criteria were classified as non-responders. Relapse was defined as reappearance of cytopenia, blood infiltration, or increase in the percentage of Table 1 Patient demographics hairy cells originally found in the bone marrow biopsy. Untreated Previously Total Toxicity was graded by standard World Health Organiza- treated tion (WHO) criteria. Second malignancies appearing after DCF treatment were recorded. Follow-up intervals varied Number 84 154 238 depending on habit of each center, but all patients were exam- Age ined at a minimun of 6-month intervals. Bone marrow exam- Median (years) 61.1 60 60.2 inations were not routinely performed unless cytopenia reap- Range 31–86 33–85 31–86 peared but all patients underwent at least two bone marrow Sex controls over the first 3 years. Lymphocyte subsets were not Male 68 124 192 Female 16 30 46 monitored after therapy. Disease duration before DCF Median (months) 0 34.8 — Range — 1–365 — Statistical methods Treatment before DCFa Splenectomy 0 31 31 Overall survival (OS) was considered as the time from the date Interferon 0 157 157 2-CdA 0 6 6 of first DCF infusion until death from any cause or date of last CHOP, chlorambucil 0 5 5 observation. Disease-free survival (DFS) was defined as the Clinical spleen size time from the date of response until relapse, or death, or date No splenomegaly 43 80 123 of last observation. Survival curves were drawn according Mild (р5 cm) 20 32 52 to Kaplan and Meier12 and differences in response were Massive (Ͼ5 cm) 15 13 28 estimated by the log-rank test. Lymphadenopathy 7 11 18 Peripheral blood hematologic Response, DFS and OS were analyzed using univariate Ͻ parameters analysis for each of the following covariates: (1) age ( 51 Median neutrophil (109/l)b 0.78 1.1 0.97 years, 51 years); (2) sex; (3) time from diagnosis of HCL to Range 0–8.03 0–4.5 0–8.03 DCF therapy; (4) previous therapy (including splenectomy Median hemoglobin level 109 128 123 and/or systemictreatment); (5) splenomegaly (yes/no); (6) (g/lb) 5–168 34–168 Ͻ Range 34–156 101 96 adenopathy (yes/no); (7) Hemoglobin level ( 100 g/l, 100 g/l); 9 b Ͻ × 9 × 9 Ͼ × Median platelets (10 /l) 83 18–396 13–507 (8) white blood cell count ( 2 10 /l, 2–4 10 /l, 4 Range 13–507 9 Ͻ × 9 × 9 Ͼ 10 /l); (9) neutrophil count ( 1 10 /l, 1–1.5 10 /l, 1.5 Bone marrow infiltration × 109/l); (10) hairy cells in peripheral blood (yes/no); (11) plat- (percentage)b elet count (Ͻ100 × 109/l, 100 × 109/l); (12) bone marrow Median 48.5 31.5 40 fibrosis (0, +, ++/+++, ++++). Range 5–100 1–100 1–100 Multivariate analysis on response, DFS, and OS was also Peripheral blood 13 immunophenotype profile performed using Cox proportional hazard models. The Typical hairy cell leukemia 84 148 232 above-mentioned factors were included in the model as Atypical hairy cell leukemia 0 6 6 explanatory variables. First a multivariate analysis using stepwise method to select variables with significance level of 0.05 a40 patients received two or three different treatments before DCF. was performed. In addition of selected variables, an analysis bThe two groups of patients were significantly different by para- was performed with a full model, including all the covariates meter.

Leukemia Pentostatin in hairy cell leukemia F Maloisel et al 47 feron-␣ alone (137 patients), splenectomy alone (10 patients), Relapse and retreatment results both interferon-␣ and splenectomy (21 patients), 2CdA (6 patients), and other chemotherapy (CHOP or chlorambucil) (5 Thirty-four of 220 patients (15%) who achieved a response patients). Forty patients had more than two previous treat- experienced disease recurrence; 26 of 182 complete ments. Pretreatment hematologicfeatures are shown in Table responders (14.3%) had recurrence at a median of 56 months 1. Six patients lacked expression of CD25 and were classified (range, 11–89 months) and eight of 38 partial responders as variant form of HCL. Bone marrow analysis showed a (21%) relapsed at 12 months (range, 3–80 months). Median median percentage of hairy cells infiltration of 40% (range, 1– time to first relapse was 41 months (range, 3–89 months). 100%). Severe bone marrow fibrosis (+++/++++) on biopsy Time to relapse was significantly shorter for patients in partial was noted in 35 cases over 176 evaluated patients (20%). response (P Ͻ 0.05). Median follow-up duration for the whole population since Of the 34 patients who relapsed, two received no further the first DCF infusion was 63.5 months (range, 0.39 to 138.4 therapy, 10 were retreated with DCF, two received interferon, months). However, the median follow-up since the diagnosis one received fludarabine, and 19 received 2CdA. Response of HCL was 102 months (range, 6 to 370 months). The oldest information after a second DCF therapy is available for all diagnosis of HCL was done in July 1967. patients. Of the patients who received second courses of DCF at first relapse, eight achieved CR and two PR. Cladribine induced 14 objective response included 11 CR. Two patients Response died during treatment, one did not respond, and two were not evaluable. Of the 238 patients treated with pentostatin, 230 patients could complete the treatment schedule and were evaluable for response and all were evaluable for toxicity. Among the Acute toxicities 10 nonevaluable patients for response, seven had discontinued the therapy after three cycles (n = 5) and two cycles (n Lethal acute and delayed toxicities are separately reported. = 2), respectively, because of severe toxicity, and three Patients with pre-existing profound cytopenia were not taken patients died during therapy (less than three cycles). After a into account during the first 2 months of treatment. Sixteen median of nine cycles of pentostatine (range, 1–19 cycles), patients experienced grade 3 neutropenia and two had grade 152 of 230 patients achieved CR and 30 CRu (79.1%), and 4 neutropenia. Twenty-nine patients experienced grade 3 38 (16.5%) achieved partial response, for an overall response thrombocytopenia and six had grade 4 thrombocytopenia. rate of 95.5% (95% CI, 89–100). Response rates to pentostat- Grade 3 anemia was noted in 16 patients and two had grade ine were independent of prior therapy (Table 2). 4 anemia. Of the 38 patients who achieved a partial response, 35 had Of the 238 treated patients, 40 (17%) developed neutro- residual disease in the marrow in the absence of splenomegaly penicfever (temperature Ͼ38.5°C) and 13 (5.5%) had docu- on physical examination or peripheral blood cytopenias. mented infections leading in three cases to toxic death. The Three partial responders had persistent marrow disease most common bacterial infection was staphylococcal (S. associated with residual splenomegaly. aureus, five cases; coagulase negative Staphylococcus, three Ten patients were nonresponders after six DCF cycles. One cases), six patients with septicemia, and two grew Stapholoc- received a bone marrow allograft and died during aplasia, the occus from the skin of associated cellulitis. Single patients remaining patients received one cycle of 2CdA and showed developed Enterobacter and Escherichia coli. Three patients three CR and four PR. The last two patients died during developed dermatomal herpes zoster. There were no acute aplasia. fungal infections. Two patients experienced two paroxysmal In the multivariate analysis, two pretreatment variables were atrial tachycardia and one a severe pulmonary embolism. shown to adversely influence the achievement of CR: Hb value less than 100 g/l (P = 0.0079) and a leukocyte count less than 2 × 109/l (P = 0.0137). However, patients of more Delayed adverse events and second malignancies than 55 years of age at the beginning of the treatment with DCF tended to have a lesser chance of obtaining a CR (P = Dermatomal herpes zoster was the most frequent late infec- 0.07). tion (13 cases). One patient developed mycobacterium tuberculosis infection. After pentostatin, 18 (14 males) of 238 patients developed Table 2 Response to DCF in accordance with pre-regimen therapy second malignancies (7.5%): four non-Hodgkin’s lymphoma, three adenocarninoma of prostate, two adenocarcinoma of De novo Previously treated colon, one adenocarcinoma of breast, two basocellular carcinoma of skin, one spinocellular carcinoma of skin, two epi- n% n % dermoid carcinoma of eosophagus, one lung carcinoma, and one multiple myeloma. From the 18 patients, eight were pre- Complete remissionb 67 82.7 115 77.2 Partial remission 9 11.1 29 19.5 viously untreated, seven had received interferon, and three Refractory 5 6.2 5 3.3 had undergone splenectomy and interferon (Table 3). Median age at diagnosis of second cancer was 70 years 81a 100 149a 100 (range, 50 to 77 years), median time from diagnosis of the hairy cell leukemia to the second cancer was 64 months aResults on 230 evaluable patients. bComplete remission included complete response and uncon- (range, 7 to 267 months), median time from the pentostatin firmed complete response. The difference was not significant administration to the second cancer was 44 months (range, 7 between de novo and previously treated patients (␹2 = 3.0689, P to 80 months), and median survival time from diagnosis of the = 0.2156). second cancer was 12 months (range, 2 to 56 months).

Leukemia Pentostatin in hairy cell leukemia F Maloisel et al 48 Table 3 Second malignancies observed during the period of follow-up after DCF treatment of hairy cell leukemia

Type of second cancer HCL therapy Age at diagnosis Time from Time from DCF Survival after Status at the prior to DCF of second cancer diagnosis of HCL to second cancer diagnosis of last follow-up (years) to second cancer (months) second cancer (months) (months)

T large cell lymphoma None 71 20 20 2 Dead B large cell lymphoma Sp + IFN 50 62 9 3 Dead B large cell lymphoma None 67 180 180 12 Alive Mantel zone lymphoma None 74 7 7 35 Alive Myeloma None 59 54 54 1 Alive Adenocarcinoma, colon IFN 70 70 10 13 Dead Adenocarcinoma, colon IFN 63 192 48 7 Alive Cancer of oesophagus Sp + IFN 70 267 76 9 Alive Adenocarcinoma, prostate None 67 64 64 18 Alive Adenocarcinoma, prostate IFN 68 64 56 23 Alive Adenocarcinoma, prostate IFN 68 72 36 30 Alive Adenocarcinoma, breast IFN 67 75 48 32 Alive Epidermoid, lung Sp + IFN 67 80 123 12 Dead Epidermoid, lung IFN 59 56 20 17 Dead Basal skin cell cancer IFN 73 126 78 15 Alive Basal skin cell cancer None 77 68 68 1 Alive Basal skin cell cancer None 73 14 13 56 Alive Spinal skin cell cancer None 75 32 32 24 Alive

Sp, splenectomy; IFN, interferon.

The expected number of second primary tumors in this megaly, marrow ﬁbrosis, disease phase and platelet count. group of 238 patients is 14.7, based on calculations derived From multivariate stepwise Cox regression analysis, hemoglo- from the data of the French cancer registry. Second cancers bin level Ͻ100 g/l, white blood cell count Ͻ2 × 109/l, and were observed in 14 patients, so the excess frequency presence of nodes involvement were found to be signiﬁcant (observed-to-expected ratio) was 0.95 (95% CI, 0.5 to 1.92). predictors of reduced survival (P Ͻ 0.02) (Figures 1, 2 and 3).

Deaths Discussion

Of the 238 treated patients, 25 (10.5%) expired at a median The introduction of purine analogs in the treatment of HCL of 23 months (range, 1 to 138 months) after at least one cycle resulted in the highest CR rates registered to date for patients of pentostatin. Five died of second malignancies, five of events with this disease. With regard to DCF, the first agent capable directly related to hairy cell leukemia, four of cardiovascular of producing complete and durable remissions in patients with or cerebrovascular events, seven of infectious complications, HCL,15,16 its use was associated with significantly higher one of respiratory distress, and in three cases the cause of response rates than splenectomy or ␣-interferon, the front-line death was unknown. treatment modalities for patients with HCL in the two previous decades. Confirming the results from other groups,6,17 the current study shows the high effectiveness of DCF in HCL patients Disease-free (DFS) and overall survival (OS) either as fist-line therapy or after other therapeuticmodalities, in whom it produced a CR rate of 79.1% and an overall The median DFS for the 220 responder patients was not reached at 10 years. The estimated 5-years and 10-years DFS were 88.1% (95% CI, 82–95%) and 68.8% (95% CI, 58–82%). After univariate screening, five baseline covariates possibly predictive of DFS were entered into a proportional hazards regression model: sex, disease phase, age at first DCF infusion, white blood cell count, and hemoglobin level (in order of increasing significance). White blood cell count Ͻ2 × 109/l, hemoglobin level Ͻ100 g/l, and age at diagnosis Ͼ55 years were significant predictors of shorter DFS (P Ͻ 0.02) in the multivariate model. Of the 238 eligible patients, 25 died. Kaplan–Meier esti- mates of survival were 89.4% (95% CI, 82–96) at 5 years and 88.7% (95% CI, 81–95) 10 years after initiation of treatment. Survival outcomes were similar for patients initially treated with DCF and those previously treated (log-rank, P = 0.86). In Figure 1 Relapse-free survival of the whole population. Figure contrast to DFS, nine baseline covariates influenced survival shows estimated distributions of relapse-free survival from date of from univariate screening: hemoglobin level, adenopathy, response. Tick marks indicate patients who were alive without report white blood cell count, age at first DCF infusion, sex, spleno- of relapse at the last contact.

Leukemia Pentostatin in hairy cell leukemia F Maloisel et al 49 the 85% (95% CI, 80%-91%) from Finn et al. Moreover, it is of note that second favorable responses could be obtained with DCF retreatment and cladribine therapy in such patients induced 16 CR over 17 treated patients.17 Furthermore, six patients with refractory or relapsing disease after cladribine were treated with DCF and showed a response in five cases. This suggested a possible lack of cross-resistance between cladribine and DCF despite structural and mechanistic similarities between the two agents. Median overall and relapse-free survival in this population has not yet been reached. Estimated 5- and 10-years overall survival rates of 89% and 88%, respectively, represent a significant prolongation of life. Our results were similar to other studies even the largest one.10,11,17 We did not confirm that Figure 2 Overall survival of the whole population. Figure shows estimated distributions of overall survival from date of first DCF patients younger than 55 years of age had a more favorable infusion. Tick marks indicate patients who were alive at the last survival. However, this study showed that patients who contact. presented an hemoglobin rate under 100 g/l, or leukopenia less than 2 × 109/l, or lymph node involvement had a significant reduction of life expectancy. Thus, compared with patients in the study of Finn et al, our patients had more advanced disease with two-thirds of them previously treated patients, and 18 of them had internal adenopathy which is rare at diagnosis and appears to be related to disease duration. Furthermore, unfavorable outcome associated with adenopathy was previously described.19 The mortality experience of the patients in this study was very close to that predicted for the general population. However, mortality was greater in patients with hairy cell leukemia than in the general population in a retrospective analysis of 350 patients, primarily because of disease-related infection and second malignancies.20 Treatment with DCF was usually well tolerated. Myelo- suppression was the most frequent side-effect associated with Figure 3 Overall survival is significantly better for patients without the use of DCF.21,22 Thus, marked neutropenia, anemia and adenopathy. P = 0.02. Figure shows estimated distributions of overall thrombocytopenia were registred in 8%, 8% and 15% of survival from date of first DCF infusion, by absence (a) or presence patients, respectively. It should be stressed that serious infec- of adenopathy (b). Tick marks indicate patients who were alive at the tious complications were registered in 13 patients and led to last contact. death in three patients from septic shock. In two other cases, therapy had to be discontinued because of marked neutro- response rate of 96% associated with substantial, long-term penia. Such findings are in accordance with the results disease-free survival. reported from other studies.6,10,11,21 The prophylactic use of In the current series, the prognostic factors that adversely growth factor in patients with neutropenia at the start of the influenced the achievement of CR were a hemoglobin less treatment should be proposed. Granulocyte colony-stimulat- than 100 g/l, a white blood cell count Ͻ2 × 109/l, and greater ing factor (G-CSF) has been safely administered to patients age. The above negative prognostic factors with the exception with HCL, normalizing absolute neutrophil counts in some. of splenomegaly are in accordance with those found by However, a phase II study with comparison to historical con- Grever et al in a randomized study.17 Our results are different trols, failed to detect any clinical advantage from the use of from those found by Monserrat et al.10 In a retrospective study, filgrastim with cladribine in the treatment of HCL.23 they showed that splenectomy and a poor performance status It has been previously reported that DCF, as other purines adversely influence the CR rate. Such differences may be analogs, induces a severe and long-lasting immunosuppres- explained through differences in the characteristics of the sion state by decreasing CD4+ lymphocytes and this may have patients included in the studies. Thus, compared with patients increased the incidence of secondary malignancies and her- in the study by Grever et al, our patients and those from the pes zoster infection.24 In the present data, 16 patients had her- Spanish study, had more advanced disease, and Ͼ50% of pes infection, and 18 developed a second malignancy (7.5%), them had been treated previously with either splenectomy, a figure slightly lower than the 10% rate reported by Ribeiro interferon, or both. However, in the current series, DCF pro- et al11 and Finn et al.17 Recently the Italian group reported duced a similar CR rate in untreated and previously treated data on 1022 patients treated by splenectomy and/or IFN, and patients. Finn et al17 reported results from 241 patients with showed that the cumulative risk of development of a second a CR rate of 72%. The same result was reported by the Spanish cancer was 5%, 10%, and 14% at 5, 10, and 15 years, group over 78 patients.10 The overall response rate of nearly respectively, but not associated with a significant increased 96% was similar to the results from other studies with DCF or risk of additional second malignancies.25 Kurzrock et al20 cladribine.6,9,18 Such responses generally were durable, with demonstrated an increase in the number of second cancers, only 26 of the 182 complete responders having experienced however it was not associated with therapy. On the contrary, disease recurrence after a median follow-up of 56 months and Au et al26 reported an increased relative risk of second cancer a disease-free survival of 87% at 5 years which is similar to among men of 2.91 (P Ͻ 0.001) related to immunosuppres-

Leukemia Pentostatin in hairy cell leukemia F Maloisel et al 50 sion due to HCL or its treatment. Our data confirmed that Purpan Toulouse (Schlaifer D, Payen C). We are indebted to the incidence of subsequent malignancies was not higher than Mrs Susan Dale who edited the manuscript and to I Cimarrosti expected in the general population and were consistent with who performed statistical analysis. This work was supported the report of Finn on a comparative population of HCL by a grant from Jansen-Cilag, France. patients. However, continued folow-up of these patients is important to determine whether the risk continues to increase with time. Finally, HCL patients now have an excellent prog- References nosis, as reflected by an almost 85% survival rate at 10 years. Even so, increased mortality still exists, predominantly due 1 Bouroncle BA. Leukemic reticuloendotheliosis (hairy cell to infection. leukemia). Blood 1979; 53: 412–436. Cladribine, an adenosine deaminase-resistant purine ana- 2 Troussard X, Maloisel F, Flandrin G. Hairy cell leukemia. What is log, also produced long-term remissions.27 Direct compari- new forty years after the first description? Hematol Cell Ther 1998; sons of the current results with those produced by cladribine 40: 139–148. are difficult. However, the estimated probability of survival at 3 Maloisel F, Andre`s E, Troussard X, Herbrecht R, Dufour P. Aspects the´rapeutiques de la leuce´mie a` tricholeucocytes. Presse Med 48 months in this trial (95% (95% CI, 94%–98%)) is similar 1999; 28: 1887–1894. to what has been reported in the American study (93% (95% 4 Saven A, Piro L. Newer purine analogues for the treatment of hairy CI, 89%–96%)) and in study with cladribine (96% (95% CI, cell leukemia. N Engl J Med 1994;,330: 691–697. 94%–98%)).2 In a non-randomized study, the results from the 5 Gollard R, Lee TC, Piro LD, Saven A. The optimal management Royal Marsden Hospital suggested that the disease-free inter- of hairy cell leukemia. Drugs 1995; 49: 921–931. val is shorter after cladribine than with pentostatine.9 Further- 6 Grever M, Kopecky K, Foucar MK, Head D, Bennett JM, Hutchison RE, Corbett WEN, Cassileth PA, Habermann T, Golomb H, Rai K, more, our data confirm the lack of cross-resistance between Eisenhauer E, Appelbaum F, Cheson BD. Randomized comparison the two drugs. of pentostatin versus inteferon alfa-2a in previously untreated It is less clear as to whether any patients can be considered patients with hairy cell leukemia: an intergroup study. J Clin Oncol as cured. Yet, no plateau on the disease-free survival curves 1995; 13: 974–982. has been observed either from our study or from other 7 Cassileth PA, Cheuvart B, Spiers ASD, Harrington DP, Cumming reported series. However, the reduction of life expectancy for FJ, Neiman RS, Bennett JM, O’Connel MJ. Pentostatin induces durable remissions in hairy cell leukemia. J Clin Oncol 1991; 9: patients presenting with HCL is very small and could be 243–246. evaluated at between a 5 and 10% decrease. 8 Kraut EH, Grever MR, Bouroncle BA. Long-term follow-up of Currently, it is not known whether DCF or CdA are the treat- patients with hairy cell leukemia after treatment with 2Ј-deoxyco- ments of choice for patients with HCL, given a similar formycin. Blood 1994; 84: 4061–4063. response rate and similar toxicity produced by these two 9 Dearden CE, Matutes E, Hilditch BL, Swanbury GJ, Catowsky D. drugs. The results of the current study confirm the effectivness Long-term follow-up of patients with hairy cell leukemia after treatment with pentostatin or cladribine. Br J Haematol 1999; 106: and acceptable toxicity profile of DCF treatment for patients 515–519. with HCL. Leucopenia, anemia and adenopathies were factors 10 Montserrat R, Cervantes F, Beltran JM, Zuazu F, Nieto LH, Rayon of poor outcome. In the absence of a comparative study, the C, Talavera JG, Monserrat E. Deoxycoformycin in the treatment choice of which agent to use largely depends on availability, of patients with hairy cell leukemia. Results of a spanish collabor- cost, and patient convenience. A 7-day continuous infusion ative study of 80 patients. Cancer 2000; 88: 352–357. of cladribine would be less convenient to the patient as com- 11 Ribeiro P, Bouaffia F, Peaud PY, BlancM, Salles B, Salles G, Coiffier B. Long-term outcome of patients with hairy cell leukemia pared to pentostatin administration. However, there are still treated pentostatin. Cancer 1998; 85: 65–71. some patients who initially or eventually fail to respond to 12 Kaplan EL, Meier P. Nonparametricestimation from incomplete purines analogs and, thus, there is a need for alternative treat- observations. J Am Stat Assoc 1958; 53: 457–481. ment modalities such monoclonal chimeric antibody against 13 Cox DR. Regression models and life-tables (with discussion). JRoy antigen CD20 or CD22.28,29 Stat Soc Ser B 1972; 34: 187–220. 14 Colonna M, He´delin G, Este`ve J, Grosclaude P, Launoy G, Buemi A, Arveux P, Tretarre B, Chaplain G, Lesec’h, Raverdy N, Carli PM, Menegoz F, Faivre J. National cancer prevalence estimation Acknowledgements in France. Int J Cancer 2000; 87: 301–304. 15 Spiers ASD, Parekh SJ, Bishop MB. Hairy cell leukemia: induction The following institutions (with main investigators) partici- of complete remission with pentostatine (2-deoxycoformycin). J pated in the study: Hopital de l’Hotel-Dieu, Paris (Chauvenet Clin Oncol 1984; 2: 1336–1342. L); Centre Hospitalier de Chalon s/Saone (Salles B, Baudet- 16 Kraut EH, Bouroncle BA, Grever MR. Pentostatine in the treatment of advanced hairy cell leukemia. J Clin Oncol 1989; 7: 168–172. Klepping S); Centre Hospitalier de Troyes (Dines G, Brahimi 17 Finn IW, Kopecky KJ, Foucar MK, Head D, Bennett JM, Hutchison S); Centre Hospitalier du Nord Mayenne (Duquesnel F); R, Corbett W, Cassileth P, Habermann T, Golomb H, Rai K, Eisen- Centre Hospitalier de Lorient (Moreau Ph); Centre Hospitalier hauer E, Appelbaum F, Cheson B, Grever MR. Long-term follow- d’Alençon (Frenkiel N); Hopital Percy Paris (Nedelec G, De up of remission duration, mortality, and second malignancies in Revel T); Centre Hospitalier de Colmar (Kohser F); HIA St hairy cell leukemia patients treated with pentostatin. Blood 2000; Anne Toulon (de Jaureguiberry JP); Hopital ND du Bon Sec- 96: 2981–2986. 18 Saven A, Burian C, Koziol JA, Piro LD. Long-term follow-up of ours Metz (Christian B); Centre Hospitalier Le Mans (Dugay patients with hairy cell leukemia after cladribine treatment. Blood J); Centre Hospitalier Blois (Rodon Ph); Hopital Pontchalliou 1998; 92: 1918–1926. Rennes (DauriacC); Centre Hospitalier Mulhouse (Eisenmann 19 Hakimian D, Tallman S, Hogan DK, Rademaker AW, Rose E, JC); Hopital Purpan Toulouse (Gaches F, Arlet-Suau E); CHU Nemcek AA. Prospective evaluation on internal adenopathy in a Lille (Noel MP, Bauters F); Clinique C Bernard Albi (Gaspard); cohort of 43 patients with hairy cell leukemia. J Clin Oncol 1994; Centre Hospitalier Be´ziers (David S); Centre Hospitalier Car- 12: 268–272. 20 Kurzrock R, Strom SS, Estey E, O’Brien S, Keating MJ, Jiang H, cassonne (Vives JF); CHU Grenoble (Pegourie B); CHU Poiti- Adams T, Talpaz M. Second cancer risk in hairy cell leukemia: ers (Desmaret MC, Guilhot F); Hopital St Antoine Paris analysis of 350 patients. J Clin Oncol 1997; 15: 1803–1810. (Cheron N, Najman A); CHU Montpellier (Legouffe E); Hopital 21 Seymour JF, Talpaz M, Kurzrock R. Response duration and recov-

Leukemia Pentostatin in hairy cell leukemia F Maloisel et al 51 ery of CD4+ lymphocytes following deoxycoformycin in L, Chisesi T, Pagnucco G, Invernizzi R, Spriano M, Resegotti L, interferon-␣-resistant hairy cell leukemia: 7-year follow-up. Leuke- Bendandi M, Damassio EE. Risk of second cancer in patients with mia 1997; 11: 42–47. hairy cell leukemia: long-term follow-up. J Clin Oncol 2002; 20: 22 Golomb HM, Dodge R, Mick R, Budman D, Hutchinson R, Horn- 638–646. ing SJ, Schiffer CA. Pentostatin treatment for hairy cell leukemia 26 Au WY, Klasa RJ, Gallagher R, Le N, Gascoyne RD, Connors JM. who failed initial therapy with recombinant alpha-interferon: a Second malignancies in patients with hairy cell leukemia in British report of CALGB study 8515. Leukemia 1994; 8: 2037–2040. Columbia: a 20-year experience. Blood 1998; 92: 1160–1164. 23 Saven A, Burian C, Adusumalli J, Koziol J. Filgranstim for cladrib- 27 Cheson BD. Infectious and immunosuppressive complications of ine-induced neutropenia fever in patients with hairy cell leukemia. purine analog therapy. J Clin Oncol 1995; 13: 2431–2448. Blood 1999; 93: 2471–2477. 28 Kreitman RJ, Wilson WH, Bergeron K, Raggio M, Stetler-Stevenson 24 Cheson BD, Sorensen JM, Vena DA, Montello MJ, Barrett JA, Dam- M, Fitzgerald DJ, Pastan I. Efﬁcacy of the anti-CD22 recombinant asio E, Tallman M, Annino L, Connors J, Coifﬁer B, Lauria F. Treat- immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. ment of hairy cell leukemia with 2-chlorodeoxyadenosine via the N Engl J Med 2001; 345: 241–247. group C protocol mechanism of the national Cancer Institute: a 29 Hagberg H, Lundholm L. Rituximab, a chimeric anti-CD20 mono- report of 979 patients. J Clin Oncol 1998; 16: 3007–3015. clonal antibody, in the treatment of hairy cell leukemia. Br J 25 Federico M, Zinzani PL, Frassoldati A, Vinceti M, Mode` A, Annino Haematol 2001; 115: 609–611.

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