D. Benfenati

Fludarabine in patients with advanced and/or resistant B-chronic lymphocytic leukemia

Abstract:  In this study, we evaluated the efficacy of fludarabine (FLU), an adenine nucleoside analogue, in 35 previously treated patients with advanced and progressed B‐cell chronic lymphocytic leukemia (B‐CLL) and in 6 at diagnosis. All patients were treated at a dose of 25 mg/m2 per day for 5 consecutive days (mean number of courses was 5, with a range from 4 to 6). The majority of patients experienced a beneficial effect on hematological parameters. In particular, a remarkable reduction of lymphocyte count together with an increase of neutrophils and platelets was observed. The overall response rate was 42% with 1 complete response and 16 partial responses. Ten patients achieved minor responses and the remaining 14 showed no benefit from treatment. An increased response rate was achieved in 6 untreated patients who showed an overall response rate of 67% (4/6). The major complications observed were neutropenia (66%) and febrile episodes (44%) that were generally infection‐related and were fatal in 3 cases. Because we were dealing with patients whose disease was advanced and/or resistant to treatment, the overall results may be considered encouraging with acceptable toxic reactions not superior to those frequently observed with polychemotherapy.

Rapid restoration of natural killer activity following treatment with 2-chlorodeoxyadenosine in 22 patients with hairy-cell leukemia

Abstract:  We report on the T‐cell profile and natural killer (NK) function in 22 hairy cell leukemia patients before and 2 and 6 months after a single 7‐day course of 2‐CdA therapy at a dose of 0.1 mg/kg daily continuous infusion. Before treatment, two groups of patients were identified in respect to NK activity, the first (12/22) had a normal number of T and NK cells and a normal NK activity, the second (10/22) showed a severe reduction of CD3 +, CD4 +, CD16 +, and CD56+ cells, together with impaired NK activity. All patients had increased serum levels of the soluble interleukin 2 receptor (sIL‐2R). Along with a high complete remission rate (77%), treatment with 2‐CdA produced a significant reduction (p = 0.001) of total lymphocytes (from 1.59 × 109/1 to 0.72 × 109/1), and particularly of CD4+ cells (from 0.68 × 109/1 to 0.23 × 109/1), while CD8+, CD16+ and CD56+ cells were less affected. Despite the dramatic reduction of lymphocytes which lasted for more than 6 months, 7/10 patients with impaired NK function before starting 2‐CdA therapy normalized the cytotoxic function within 2 months. In conclusion, 2‐CdA produces a severe reduction of lymphocytes in general, and of CD4 lymphocytes in particular, whilst it may produce a significant increase in the proportion of NK cells leading, together with a normalization of the sIL‐2R serum levels, to a rapid restoration of the NK cytotoxic function in the majority of patients.

High complete remission rate in hairy cell leukemia treated with 2-chlorodeoxyadenosine.

2-Chlorodeoxyadenosine (2-CdA), a purine nucleoside, has been shown to be remarkably effective in the treatment of patients with hairy cell leukemia (HCL). We hereby report on the results achieved in 26 HCL patients treated with one single course of 2-CdA at a dose of 0.1 mg/kg daily for 7 days continuous infusion. Twenty-four were males and 2 females, with a median age of 56 years; all but 5 had been previously treated with Interferon-alpha (IFN-alpha). All cases are fully evaluable for their clinical and hematological response. Twenty of them (77%) achieved a complete remission and 6 a partial remission; two of the latter progressed after 6 and 12 months, respectively. The median duration of response was 13.8 months, ranging from 7 to 22 months from the end of therapy. Circulating hairy cells and spleen enlargement, when present, disappeared within 2 weeks after completing treatment; furthermore, a rapid normalization of soluble Interleukin-2 receptor serum levels was observed in all complete responders but one, and in 2 of the 6 partial responders. A significant lymphocytopenia was observed in almost all patients, whilst a severe neutropenia (< 500/microliters) was registered mainly in the 10 patients who had less than 1,000/microliters neutrophils when treatment was started; the hemoglobin and platelets were marginally affected in only a few cases. Eight of the 10 patients who developed severe neutropenia experienced fever; in 4 of them it was short-lived (24 hours) and apparently not infection-related, while the remaining 4 probably had an infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum Soluble Interleukin-2 Receptor Levels in Hairy Cell Leukemia: Correlation with Clinical and Hematological Parameters and with α-Interferon Treatment

The soluble Interleukin-2 Receptor (sIL-2R) serum levels were assessed in 42 patients with Hairy-Cell Leukemia (HCL) at diagnosis and after alpha-Interferon therapy and correlated with spleen size, peripheral hematological values, hairy cell index (HCI) and clinical response. Serum sIL-2R levels were significantly increased in all HCL patients, particularly in those with a higher HCI (> 0.50) and in non-splenectomized patients. Among the 26 HCL patients who were studied before and after 12 months of alpha-IFN treatment, 16 normalized the sIL-2R level and 10 did not. Our findings suggest that sIL-2R levels in HCL patients correlate with the splenic and bone marrow tumor burden as assessed by HCI. In addition patients with low levels of sIL-2R at diagnosis appear to have a better chance of achieving a good clinical response.

Results in hairy-cell leukemia patients treated with α-interferon: Predictive prognostic factors

Abstract: Fourty‐four evaluable patients with hairy cell leukemia (HCL) were treated with human lymphoblastoid α‐interferon (α‐IFN), at a dose of 3 × 106 Units a day for 12–18 months while 18 of them continued to receive a three times per week schedule at the same dose as maintenance treatment. Eighteen percent of patients achieved complete response, 64% partial response, and 18% minor response with a median duration of 37.5, 22.9 and 3.5 months respectively. Twenty patients (45%), all partial or minor responders, subsequently had progression of the disease. The progression occurred more frequently in patients who presented at diagnosis with a hairy‐cell index value >0.50 than in those who presented with a hairy‐cell index <0.50: 14/26 (54%) versus 2/11 (18%) respectively. In addition, the progression rate was more evident in “non‐maintained” than in “maintained” patients: 16/26 (61.2%) versus 4/18 (22%). Restarting α‐IFN treatment in 16 of the 20 progressed patients proved effective only in 9 of them. From these findings it appears that a low hairy‐cell index at diagnosis correlates favorably with a good hematological response. Furthermore, continuous therapy with α‐IFN seems very useful in reducing the progression of the disease, in particular in patients with a very high hairy‐cell index at diagnosis.

Relationship between immunological phenotype and hematological response to α-IFN treatment in 35 patients with hairy cell leukemia

Abstract: During the past 6 years, clinical trials employing α‐interferon (α‐IFN) in hairy cell leukemia (HCL) have shown dramatic improvement in the management of this disease. Complete remissions (CR), however, are relatively rare (10–15%) and a minority of patients (10–25%) do not respond adequately to α‐IFN. The possibility that the poor response to α‐IFN treatment could be related to a peculiar immunological phenotype of the hairy cell (HC) was investigated in this study. The results demonstrated that, in the majority of patients who failed to respond to α‐IFN, HC showed an immunological phenotype characterized by positivity with the CD5 monoclonal antibody which is usually absent on HC and characteristically expressed on B‐chronic lymphocytic leukemia cells. In fact, among the 10 HCL patients who presented with this phenotype, only 5 partial remissions (PR) and 5 minor responses (MR) were achieved, as opposed to the 3 complete remissions (CR), 19 PR and 3 MR observed in the 25 CD5‐negative patients. The possibility that a more extensive immunological analysis of HCL patients at diagnosis may be predictive of the response to IFN treatment is postulated.

Comparison of Low-Dose versus Standard-Dose Alpha-Interferon Regimen in the Hairy Cell Leukemia Treatment

In a randomized clinical trial, the effects of standard doses of alpha-interferon (alpha-IFN) compared with the effects of half of these doses were evaluated in patients with hairy cell leukemia. There were 14 patients treated with standard-dose (3 MU/day i.m. for 6 months, then 3 MU three times/week for a further 6 months) and 10 patients with low-dose alpha-IFN (1.5 MU/day with the same schedule and for the same period). The overall response rate, the quality, and the duration of response were rather similar in both groups. The rapidity of response in normalizing the peripheral blood counts was similar, even increased in low-dose-treated patients, consisting mainly in clearing the number of circulating hairy cells (p less than 0.03). Finally, the toxic effects of both regimens were minimal but less evident in patients treated with low-dose alpha-IFN. Despite the small number of patients, on the basis of this report, we can confirm that 1.5 MU/day of alpha-IFN is an adequate treatment for patients with hairy cell leukemia.