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Long-term outcome with pentostatin treatment in hairy cell leukemia patients. A French retrospective study of 238 patients


With the introduction of new drugs such as alpha-interferon (IFN) and purine analogs, the management of hairy cell leukemia (HCL) patients has changed. However, deoxycoformycin (DCF) produced higher complete remission rates than IFN. The current study was undertaken to provide long-term data on duration of overall survival (OS) and disease-free survival (DFS) and incidence of subsequent malignancies. We retrospectively analyzed the data of patients treated with DCF (4 mg/m2/day, every 2 weeks) from 39 French centers. In 84 of 238 included patients, DCF was the first-line therapy. Pretreatment variables influencing the achievement of complete remission, DFS, and OS were identified by multivariate analysis. Two hundred and thirty-eight patients received a median of nine cycles (range, 1–19 cycles). A complete remission was obtained in 182 of 230 evaluable patients (79%) and a partial response was obtained in 38 patients, for an overall response rate of 95.6%. In the multivariate analysis hemoglobin level less than 100 g/l and leukocytes less than 2 × 109/l were parameters adversely influencing complete remission achievement. With a median follow-up of 63.5 months (range, 0.39–138.4 months), disease recurrence was observed in 34 of 220 responding patients (15%). The estimated 5-years and 10-years DFS was 88.1% and 68.8%, respectively. Hemoglobin level less than 100 g/l and leukocytes less than 2 × 109/l were the pre-treatment variables associated with a shorter DFS. The estimated 5-year and 10-year OS were 89.4% and 88.7%, respectively. Hemoglobin level less than 100 g/l, leukocytes less than 2 × 109/l, and adenopathy were significant factors of reduced survival. Hematologic toxicity was the main side-effect, followed by infection and emesis. During the period of follow-up, 18 patients developed second cancer, but the standardized incidence ratio was 0.95. Pentostatin is a highly effective regimen for hairy cell leukemia that produces durable complete responses. Toxicity of DCF is acceptable. Subsequent malignancies do not appear to be increased with pentostatin treatment.


Hairy cell leukemia (HCL) is a rare lymphoproliferative malignancy first described in 1958 and referred to originally as leukemic reticuloendotheliosis.1 The natural history of this lymphoproliferative disorder varies. Studies on HCL from 1958 to 1984 showed a median survival time of approximately 4 years before systemic effective therapy was introduced.2 Splenectomy was the first treatment modality to be regularly used in HCL and it was able to achieve a rapid peripheral hematologic reconstitution even in the presence of severe cytopenia.3 Although splenectomy decreased cytopenia, it had no effect on bone marrow infiltration, meaning that eventually another treatment was necessary. With the introduction of new drugs, such as alpha-interferon (IFN), 2′ deoxycoformycin (DCF), and 2′-chlorodeoxyadenosine (2CdA), the management of HCL patients changed. The last two were purine analogs that differ in their interaction with adenosine deaminase, the enzyme that plays a role in the purine metabolism and which is present in high concentrations in lymphoid tissues.4 The proportion of patients obtaining a response with IFN ranged from 0% to 43% for complete remission (CR) and rose to 90% for partial response (PR), but the majority of patients relapsed after stopping therapy.5 A randomized study, with a cross-over design, comparing DCF to IFN demonstrated that DCF produced a higher complete remission rate with more durable response, but without differences in terms of survival.6 Since the first publication on DCF activity in HCL patients, numerous studies confirmed this observation.7,8,9,10,11 In the first clinical trials, patients were treated with higher doses but severe neurologic adverse events were noted and, secondarily, it was reported that lower doses (4 mg/m2) was less toxic with the same efficacy.7 Recently, the appearence of second malignancies after purine analogs was regarded as a potential problem and was observed in 10% of patients treated with DCF.2

We report here a large cohort of patients with HCL treated with DCF and a median follow-up of 63.5 months.

Materials and methods

Patients, treatment schedule and criteria of response

Retrospectively, data of HCL patients from 39 French centers treated with DCF between March 1989 and December 1997 were analyzed. Data files were reviewed before inclusion in the present analysis and patients were required to have: (1) a 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 count less than 1 × 109/l, or hemoglobin level less than 100 g/l, or thrombocytopenia less than 100 × 109/l), recurrent infections, or massive splenomegaly; (3) patients required abdominal evaluation by CT scans; (4) an adequate renal and liver function (creatinin less than 1.5 N and liver enzymes less than 2.5 N); (5) patients could have been either untreated or have previously been treated with splenectomy, systemic chemotherapy, or both.

DCF was given at a dose of 4 mg/m2 by intravenous bolus injection every 2 weeks and was continued to the point of maximal response or treatment failure. No maintenance therapy was given. Any recurrence of cytopenia after the fourth course would postpone treatment until recuperation to near normal values.

Established response criteria were used and are summarized as follows: CR was defined as (1) disappearence of any evidence of HCL cell in blood and bone marrow; (2) achievement of hemoglobin level greater than 120 g/l, platelet count 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 originally present. Patients who presented all peripheral blood CR criteria except the bone marrow control were considered as unconfirmed CR (CRu). PR required all the following: (1) normal blood counts as stated above; (2) reduction of initial spleen size by more than 50%; (3) a 50% reduction or greater in the percentage of hairy cell infiltration in the bone marrow. 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 hairy cells originally found in the bone marrow biopsy.

Toxicity was graded by standard World Health Organization (WHO) criteria. Second malignancies appearing after DCF treatment were recorded. Follow-up intervals varied depending on habit of each center, but all patients were examined at a minimun of 6-month intervals. Bone marrow examinations were not routinely performed unless cytopenia reappeared but all patients underwent at least two bone marrow controls over the first 3 years. Lymphocyte subsets were not monitored after therapy.

Statistical methods

Overall survival (OS) was considered as the time from the date of first DCF infusion until death from any cause or date of last observation. Disease-free survival (DFS) was defined as the time from the date of response until relapse, or death, or date of last observation. Survival curves were drawn according to Kaplan and Meier12 and differences in response were estimated by the log-rank test.

Response, DFS and OS were analyzed using univariate analysis for each of the following covariates: (1) age (<51 years, 51 years); (2) sex; (3) time from diagnosis of HCL to DCF therapy; (4) previous therapy (including splenectomy and/or systemic treatment); (5) splenomegaly (yes/no); (6) adenopathy (yes/no); (7) Hemoglobin level (<100 g/l, 100 g/l); (8) white blood cell count (<2 × 109/l, 2–4 × 109/l, >4 × 109/l); (9) neutrophil count (<1 × 109/l, 1–1.5 × 109/l, >1.5 × 109/l); (10) hairy cells in peripheral blood (yes/no); (11) platelet count (<100 × 109/l, 100 × 109/l); (12) bone marrow fibrosis (0, +, ++/+++, ++++).

Multivariate analysis on response, DFS, and OS was also performed using Cox proportional hazard models.13 The above-mentioned factors were included in the model as explanatory variables. First a multivariate analysis using stepwise method to select variables with significance level of 0.05 was performed. In addition of selected variables, an analysis was performed with a full model, including all the covariates mentioned above. The proportional hazard assumption was validated on the most statistically significant covariates.

To determine whether there was an excess of secondary primary tumors (occurring after the diagnosis of HCL), we computed standardized incidence ratio calculated by determining the ratio of the observed to expected number of individuals with second malignancies. The expected number of individuals with secondary invasive malignancies (excluding non-melanoma skin cancer) was determined using age, sex, and calendar-year-specific incidence rate extrapolated from the main French cancer registries.14

Results presented here are based on data available as of 15 March 2001. Statistical analysis was carried out by Biotrial, Rennes, France.


Patient's characteristics

Table 1 shows the main clinical features at the start of treatment for the 238 patients included in the present study: 154 (64.7%) patients had received prior treatment, including interferon-α alone (137 patients), splenectomy alone (10 patients), both interferon-α and splenectomy (21 patients), 2CdA (6 patients), and other chemotherapy (CHOP or chlorambucil) (5 patients). Forty patients had more than two previous treatments. Pretreatment hematologic features are shown in Table 1. Six patients lacked expression of CD25 and were classified as variant form of HCL. Bone marrow analysis showed a median percentage of hairy cells infiltration of 40% (range, 1–100%). Severe bone marrow fibrosis (+++/++++) on biopsy was noted in 35 cases over 176 evaluated patients (20%).

Table 1 Patient demographics

Median follow-up duration for the whole population since the first DCF infusion was 63.5 months (range, 0.39 to 138.4 months). However, the median follow-up since the diagnosis of HCL was 102 months (range, 6 to 370 months). The oldest diagnosis of HCL was done in July 1967.


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 10 nonevaluable patients for response, seven had discontinued the therapy after three cycles (n = 5) and two cycles (n = 2), respectively, because of severe toxicity, and three patients died during therapy (less than three cycles). After a median of nine cycles of pentostatine (range, 1–19 cycles), 152 of 230 patients achieved CR and 30 CRu (79.1%), and 38 (16.5%) achieved partial response, for an overall response rate of 95.5% (95% CI, 89–100). Response rates to pentostatine were independent of prior therapy (Table 2).

Table 2 Response to DCF in accordance with pre-regimen therapy

Of the 38 patients who achieved a partial response, 35 had residual disease in the marrow in the absence of splenomegaly on physical examination or peripheral blood cytopenias. Three partial responders had persistent marrow disease associated with residual splenomegaly.

Ten patients were nonresponders after six DCF cycles. One received a bone marrow allograft and died during aplasia, the remaining patients received one cycle of 2CdA and showed three CR and four PR. The last two patients died during aplasia.

In the multivariate analysis, two pretreatment variables were 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 than 55 years of age at the beginning of the treatment with DCF tended to have a lesser chance of obtaining a CR (P = 0.07).

Relapse and retreatment results

Thirty-four of 220 patients (15%) who achieved a response experienced disease recurrence; 26 of 182 complete responders (14.3%) had recurrence at a median of 56 months (range, 11–89 months) and eight of 38 partial responders (21%) relapsed at 12 months (range, 3–80 months). Median time to first relapse was 41 months (range, 3–89 months). Time to relapse was significantly shorter for patients in partial response (P < 0.05).

Of the 34 patients who relapsed, two received no further therapy, 10 were retreated with DCF, two received interferon, one received fludarabine, and 19 received 2CdA. Response information after a second DCF therapy is available for all 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 died during treatment, one did not respond, and two were not evaluable.

Acute toxicities

Lethal acute and delayed toxicities are separately reported. Patients with pre-existing profound cytopenia were not taken into account during the first 2 months of treatment. Sixteen patients experienced grade 3 neutropenia and two had grade 4 neutropenia. Twenty-nine patients experienced grade 3 thrombocytopenia and six had grade 4 thrombocytopenia. Grade 3 anemia was noted in 16 patients and two had grade 4 anemia.

Of the 238 treated patients, 40 (17%) developed neutropenic fever (temperature >38.5°C) and 13 (5.5%) had documented infections leading in three cases to toxic death. The most common bacterial infection was staphylococcal (S. aureus, five cases; coagulase negative Staphylococcus, three cases), six patients with septicemia, and two grew Stapholococcus from the skin of associated cellulitis. Single patients developed Enterobacter and Escherichia coli. Three patients developed dermatomal herpes zoster. There were no acute fungal infections. Two patients experienced two paroxysmal atrial tachycardia and one a severe pulmonary embolism.

Delayed adverse events and second malignancies

Dermatomal herpes zoster was the most frequent late infection (13 cases). One patient developed mycobacterium tuberculosis infection.

After pentostatin, 18 (14 males) of 238 patients developed second malignancies (7.5%): four non-Hodgkin's lymphoma, three adenocarninoma of prostate, two adenocarcinoma of colon, one adenocarcinoma of breast, two basocellular carcinoma of skin, one spinocellular carcinoma of skin, two epidermoid carcinoma of eosophagus, one lung carcinoma, and one multiple myeloma. From the 18 patients, eight were previously untreated, seven had received interferon, and three had undergone splenectomy and interferon (Table 3).

Table 3 Second malignancies observed during the period of follow-up after DCF treatment of hairy cell leukemia

Median age at diagnosis of second cancer was 70 years (range, 50 to 77 years), median time from diagnosis of the hairy cell leukemia to the second cancer was 64 months (range, 7 to 267 months), median time from the pentostatin administration to the second cancer was 44 months (range, 7 to 80 months), and median survival time from diagnosis of the second cancer was 12 months (range, 2 to 56 months).

The expected number of second primary tumors in this group of 238 patients is 14.7, based on calculations derived from the data of the French cancer registry. Second cancers were observed in 14 patients, so the excess frequency (observed-to-expected ratio) was 0.95 (95% CI, 0.5 to 1.92).


Of the 238 treated patients, 25 (10.5%) expired at a median of 23 months (range, 1 to 138 months) after at least one cycle of pentostatin. Five died of second malignancies, five of events directly related to hairy cell leukemia, four of cardiovascular or cerebrovascular events, seven of infectious complications, one of respiratory distress, and in three cases the cause of death was unknown.

Disease-free (DFS) and overall survival (OS)

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 <2 × 109/l, hemoglobin level <100 g/l, and age at diagnosis >55 years were significant predictors of shorter DFS (P < 0.02) in the multivariate model.

Of the 238 eligible patients, 25 died. Kaplan–Meier estimates 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 contrast to DFS, nine baseline covariates influenced survival from univariate screening: hemoglobin level, adenopathy, white blood cell count, age at first DCF infusion, sex, splenomegaly, marrow fibrosis, disease phase and platelet count. From multivariate stepwise Cox regression analysis, hemoglobin level <100 g/l, white blood cell count <2 × 109/l, and presence of nodes involvement were found to be significant predictors of reduced survival (P < 0.02) (Figures 1, 2 and 3).

Figure 1

Relapse-free survival of the whole population. Figure shows estimated distributions of relapse-free survival from date of response. Tick marks indicate patients who were alive without report of relapse at the last contact.

Figure 2

Overall survival of the whole population. Figure shows estimated distributions of overall survival from date of first DCF infusion. Tick marks indicate patients who were alive at the last contact.

Figure 3

Overall survival is significantly better for patients without adenopathy. P = 0.02. Figure shows estimated distributions of overall survival from date of first DCF infusion, by absence (a) or presence of adenopathy (b). Tick marks indicate patients who were alive at the last contact.


The introduction of purine analogs in the treatment of HCL resulted in the highest CR rates registered to date for patients with this disease. With regard to DCF, the first agent capable of producing complete and durable remissions in patients with HCL,15,16 its use was associated with significantly higher response rates than splenectomy or α-interferon, the front-line 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 either as fist-line therapy or after other therapeutic modalities, in whom it produced a CR rate of 79.1% and an overall response rate of 96% associated with substantial, long-term disease-free survival.

In the current series, the prognostic factors that adversely influenced the achievement of CR were a hemoglobin less than 100 g/l, a white blood cell count <2 × 109/l, and greater age. The above negative prognostic factors with the exception of splenomegaly are in accordance with those found by Grever et al in a randomized study.17 Our results are different from those found by Monserrat et al.10 In a retrospective study, they showed that splenectomy and a poor performance status adversely influence the CR rate. Such differences may be explained through differences in the characteristics of the patients included in the studies. Thus, compared with patients in the study by Grever et al, our patients and those from the Spanish study, had more advanced disease, and >50% of them had been treated previously with either splenectomy, interferon, or both. However, in the current series, DCF produced a similar CR rate in untreated and previously treated patients. Finn et al17 reported results from 241 patients with a CR rate of 72%. The same result was reported by the Spanish group over 78 patients.10 The overall response rate of nearly 96% was similar to the results from other studies with DCF or cladribine.6,9,18 Such responses generally were durable, with only 26 of the 182 complete responders having experienced disease recurrence after a median follow-up of 56 months and a disease-free survival of 87% at 5 years which is similar to 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 patients younger than 55 years of age had a more favorable survival. However, this study showed that patients who 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. Myelosuppression was the most frequent side-effect associated with the use of DCF.21,22 Thus, marked neutropenia, anemia and thrombocytopenia were registred in 8%, 8% and 15% of patients, respectively. It should be stressed that serious infectious complications were registered in 13 patients and led to death in three patients from septic shock. In two other cases, therapy had to be discontinued because of marked neutropenia. Such findings are in accordance with the results reported from other studies.6,10,11,21 The prophylactic use of growth factor in patients with neutropenia at the start of the treatment should be proposed. Granulocyte colony-stimulating factor (G-CSF) has been safely administered to patients with HCL, normalizing absolute neutrophil counts in some. However, a phase II study with comparison to historical controls, failed to detect any clinical advantage from the use of filgrastim with cladribine in the treatment of HCL.23

It has been previously reported that DCF, as other purines analogs, induces a severe and long-lasting immunosuppression state by decreasing CD4+ lymphocytes and this may have increased the incidence of secondary malignancies and herpes zoster infection.24 In the present data, 16 patients had herpes infection, and 18 developed a second malignancy (7.5%), a figure slightly lower than the 10% rate reported by Ribeiro et al11 and Finn et al.17 Recently the Italian group reported data on 1022 patients treated by splenectomy and/or IFN, and showed that the cumulative risk of development of a second cancer was 5%, 10%, and 14% at 5, 10, and 15 years, respectively, but not associated with a significant increased risk of additional second malignancies.25 Kurzrock et al20 demonstrated an increase in the number of second cancers, however it was not associated with therapy. On the contrary, Au et al26 reported an increased relative risk of second cancer among men of 2.91 (P < 0.001) related to immunosuppression due to HCL or its treatment. Our data confirmed that the incidence of subsequent malignancies was not higher than expected in the general population and were consistent with the report of Finn on a comparative population of HCL 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 prognosis, as reflected by an almost 85% survival rate at 10 years. Even so, increased mortality still exists, predominantly due to infection.

Cladribine, an adenosine deaminase-resistant purine analog, also produced long-term remissions.27 Direct comparisons of the current results with those produced by cladribine are difficult. However, the estimated probability of survival at 48 months in this trial (95% (95% CI, 94%–98%)) is similar to what has been reported in the American study (93% (95% CI, 89%–96%)) and in study with cladribine (96% (95% CI, 94%–98%)).2 In a non-randomized study, the results from the Royal Marsden Hospital suggested that the disease-free interval is shorter after cladribine than with pentostatine.9 Furthermore, our data confirm the lack of cross-resistance between the two drugs.

It is less clear as to whether any patients can be considered as cured. Yet, no plateau on the disease-free survival curves has been observed either from our study or from other reported series. However, the reduction of life expectancy for patients presenting with HCL is very small and could be evaluated at between a 5 and 10% decrease.

Currently, it is not known whether DCF or CdA are the treatments of choice for patients with HCL, given a similar response rate and similar toxicity produced by these two drugs. The results of the current study confirm the effectivness and acceptable toxicity profile of DCF treatment for patients with HCL. Leucopenia, anemia and adenopathies were factors of poor outcome. In the absence of a comparative study, the choice of which agent to use largely depends on availability, cost, and patient convenience. A 7-day continuous infusion of cladribine would be less convenient to the patient as compared to pentostatin administration. However, there are still some patients who initially or eventually fail to respond to purines analogs and, thus, there is a need for alternative treatment modalities such monoclonal chimeric antibody against antigen CD20 or CD22.28,29


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The following institutions (with main investigators) participated in the study: Hopital de l’Hotel-Dieu, Paris (Chauvenet L); Centre Hospitalier de Chalon s/Saone (Salles B, Baudet-Klepping S); Centre Hospitalier de Troyes (Dines G, Brahimi S); Centre Hospitalier du Nord Mayenne (Duquesnel F); Centre Hospitalier de Lorient (Moreau Ph); Centre Hospitalier d'Alençon (Frenkiel N); Hopital Percy Paris (Nedelec G, De Revel T); Centre Hospitalier de Colmar (Kohser F); HIA St Anne Toulon (de Jaureguiberry JP); Hopital ND du Bon Secours Metz (Christian B); Centre Hospitalier Le Mans (Dugay J); Centre Hospitalier Blois (Rodon Ph); Hopital Pontchalliou Rennes (Dauriac C); Centre Hospitalier Mulhouse (Eisenmann JC); Hopital Purpan Toulouse (Gaches F, Arlet-Suau E); CHU Lille (Noel MP, Bauters F); Clinique C Bernard Albi (Gaspard); Centre Hospitalier Béziers (David S); Centre Hospitalier Carcassonne (Vives JF); CHU Grenoble (Pegourie B); CHU Poitiers (Desmaret MC, Guilhot F); Hopital St Antoine Paris (Cheron N, Najman A); CHU Montpellier (Legouffe E); Hopital Purpan Toulouse (Schlaifer D, Payen C). We are indebted to Mrs Susan Dale who edited the manuscript and to I Cimarrosti who performed statistical analysis. This work was supported by a grant from Jansen-Cilag, France.

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Correspondence to F Maloisel.

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Maloisel, F., Benboubker, L., Gardembas, M. et al. Long-term outcome with pentostatin treatment in hairy cell leukemia patients. A French retrospective study of 238 patients. Leukemia 17, 45–51 (2003).

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  • hairy cell leukemia
  • deoxycoformycin
  • long-term follow-up
  • secondary cancer

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