Treatment with low dose human recombinant interferon-alpha-2-ARG induces complete remission in patients with hairy cell leukemia

Five cases with advanced hairy cell leukemia refractory to treatment with splenectomy and chemotherapy as well as one patient presenting with a stage-A response to splenectomy were treated with rhu-IFN-alpha 2-arg. 5 X 10(6) were administered intramuscularly every day. Both patients, with advanced disease resistant to conventional therapy and treated for six or more months with rhu-IFN-alpha 2-arg, achieved complete clinical remissions. Three further cases treated for less than half a year and also with advanced disease achieved partial remission states with marked reduction of circulating hairy cells and with recovery of normal hemopoiesis. Minimal residual disease in the remaining patient during a three-month period of treatment did not respond. Side effects of rhu-IFN-alpha 2 low dose therapy were minimal in 5 cases and comprised a severe leukopenia reversible after dose reduction in one patient.     

Current treatment options in hairy cell leukemia and hairy cell leukemia variant

Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder characterized by splenomegaly, pancytopenia and circulating lymphocytes displaying prominent cytoplasmic projections. HCL has usually an indolent course and the patients with asymptomatic disease do not require therapy. Treatment of progressive symptomatic HCL includes a variety of pharmacological approaches such as interferon-alpha (IFN-alpha), pentostatin (DCF) and cladribine (2-CdA), which have significantly improved the disease prognosis. 2-CdA and DCF seem to induce a similar high response rate and a long overall survival. They are also active in relapsed patients. More recently high activity of anti-CD20 monoclonal antibody (rituximab) and anti-CD25 (LMB-2) and anti-CD22 (BL-22) immunotoxins have increased the number of therapeutic options for HCL. Splenectomy may be still indicated in patients with massive, symptomatic splenomegaly or results in severe cytopenia. IFN-alpha may have a place in patients with very severe cytopenia, in HCL in pregnancy and in patients who have failed prior therapy with purine nucleoside analogs. HCL variant (HCL-V) is a distinct clinico-pathological entity which seems to be resistant to IFN-alpha and purine nucleoside analogs - DCF and 2-CdA. However, preliminary observations suggest that monoclonal antibodies - rituximab and BL-22 immunotoxin are highly active in this disorder even refractory to 2-CdA. In this review current therapeutic strategies in HCL and HCL-V are presented.     

Cytogenetic studies in patients with hairy cell leukemia

We performed cytogenetic studies on 58 patients with hairy cell leukemia (HCL) from 1975 to 1981. Analysable metaphase cells stained with Q-banding were obtained in 77 samples from 44 patients. Cells with abnormal chromosomes were found in both unstimulated and stimulated cultures of bone marrow and peripheral blood. Patients were classified in 6 groups. Group I, 2 patients with a clonal chromosome abnormality; group II, 13 patients with nonclonal structural abnormalities; group III, 5 patients with nonclonal numerical abnormalities; group IV, 19 patients with only a normal karyotype; group V, 15 patients with no or with fewer than 5 normal metaphase cells; group VI, 4 patients with questionable abnormal chromosomes. Common abnormalities were deletion of the long arm of No. 6 or +3 each in 3 patients, and +Y, +12 or +18 in 2 patients. Actuarial survival for each group was calculated from diagnosis and also from chromosome examination. The two patients with a clonal chromosome abnormality died within one year. Eight of 13 patients with nonclonal structural abnormalities died within 5 years after diagnosis, while none of 5 patients with nonclonal numerical abnormalities and 2 of 19 patients with normal chromosomes died within 5 years. The difference in the 5-year actuarial survival between patients with nonclonal abnormalities (groups II and III) and those with a normal karyotype was significant (p<0.05). The difference was more marked between patients with nonclonal structural abnormalities and those with a normal karyotype (p<0.01). Patients with nonclonal numerical abnormalities had a longer survival than those patients with nonclonal structural abnormalities (p<0.05). Thus, structural chromosome abnormalities in HCL may be a poor prognostic sign even when they are not clonal.     

Randomized study of the duration of treatment with interferon alfa-2B in patients with hairy cell leukemia

Several previous studies have demonstrated that both partially purified and recombinant alpha-interferons (alpha-IFNs) have high response rates in advanced hairy cell leukemia. However, the optimal dose and duration of therapy have not yet been defined. In this study, 90 patients were randomized after 12 months of IFN alfa-2b therapy with a standard dose of 2 X 10(6) U/m2 sc three times weekly to either no further therapy or an additional 6 months of therapy (18 mo total). There was no significant difference in the peripheral blood cell counts between the two groups (when analyzed) dating from the end of IFN therapy rather than from the time of randomization. Eighteen evaluable patients relapsed and were re-treated with IFN: 11 in the no-further-therapy group and 7 in the treated group. No patient was resistant to re-treatment with IFN. There was a significantly greater incidence of fatigue in the treated group (44% vs. 21%; P = .02) during the first 6 postrandomization months. We conclude that the duration of IFN therapy does not influence the clinical course after therapy is discontinued, but responses are maintained while patients receive therapy. However, because of a high incidence of fatigue with prolonged therapy and the ability to reinduce a second response, we recommend that IFN therapy be discontinued after 12 months in asymptomatic patients.     

Chromosome abnormalities in patients with hairy cell leukemia

We evaluated chromosomes from 20 patients with hairy cell leukemia (HCL) to ascertain the frequency and type of consistent chromosomal abnormalities. Samples from 17 patients were obtained from peripheral blood cultures grown 24 and 48 hours without phytohemagglutinin, or from bone marrow samples. Two male patients had similar, consistent abnormalities; one patient's karyotype was 46,X,+12; that of the second was 46,X,+C marker. In the latter case, the distal long arm of the C marker most closely resembled chromosome No. 12 from band q14 to q terminal, but the short arm and proximal long arm were of undetermined origin. Both karyotypes lacked the Y chromosome. A third patient had, in one sample, a single abnormal cell with an extra No. 3 and an extra No. 12 (48,XY,+3,+12), and in a later sample, a second cell of poor morphology which also could have been trisomic for no. 12. The two patients with consistent chromosome abnormalities had rapidly progressive disease and a relatively short clinical course from the time of diagnosis (5 and 7 months, respectively). Further data are needed, but the results thus far suggest that patients with consistent chromosome abnormalities could be considered as candidates for aggressive combination chemotherapy.     

Long-term effects of 2'-deoxycoformycin treatment on cytokine production in patients with hairy cell leukemia.

Deoxycoformycin (DCF) has been reported to cause immediate reduction and dysfunction of T lymphocytes, but the long-term effects on immune functions are still not known. As cytokine production is regulated by T helper-inducer lymphocytes and might represent a parameter for functional integrity of immunocompetent cells, we have measured the production of interleukin-2 (IL-2), tumor necrosis factor (TNF), and interferons (IFN) by peripheral mononuclear cells (PMNC) from 10 patients with hairy cell leukemia 11-24 months after end of therapy with DCF. The patients were in continuous remission at the time of study. Despite an absolute reduction in CD3+ and CD4+ lymphocytes. there were no significant differences in IL-2 or TNF release between patients and controls. Except for a significant reduction in IFN-alpha release stimulated by Newcastle disease virus (NDV), IFN productions induced by other mitogens (phytohemagglutinin, PHA; Concanavalin A, ConA; pokeweed mitogen, PWM) and viral antigens were within normal range. There was also a decrease in proliferative responsiveness to PHA, but responses to ConA, PWM, and other viral antigens were normal. In five of the patients, we have monitored closely the changes in IL-2, TNF, and IFN before, during, and after treatment and could demonstrate a rapid normalization of initially decreased IL-2 release in all cases and also of TNF if the initial production was reduced. This study shows that, even though the absolute number of T lymphocytes and helper cells are reduced in the long-term observation after DCF treatment, the capacity to produce IL-2, TNF, and IFN-gamma was within normal range. Parallel to this observation, no opportunistic infections or frequency of infectious complications occurred in these patients.     

Extended follow-up of patients with hairy cell leukemia after treatment with cladribine.

PURPOSE: Hairy cell leukemia (HCL) is an uncommon, indolent, chronic B-cell lymphoproliferative disorder involving the marrow and spleen. Therapy for HCL includes splenectomy, interferon alfa-2a and alfa-2b, pentostatin, and cladribine. The purpose of this article was to report the extended follow-up of HCL patients treated with cladribine. PATIENTS AND METHODS: Two hundred nine patients with HCL who were treated with cladribine had at least 7 years of follow-up. A course of cladribine constituted a 7-day continuous intravenous infusion at a dose of 0.1 mg/kg/d. RESULTS: Of the 207 assessable patients who had at least 7 years of follow-up, 196 (95%) achieved a complete response (CR) and 11 (5%) achieved a partial response (PR) after a single course of cladribine (overall response rate, 100%). The median first-response duration for all responders was 98 months. Seventy-six patients (37%) experienced relapse after their first course of cladribine. The median time to first relapse for all responders was 42 months. Time to treatment failure of CRs compared with PRs was statistically significant (P <.0005). The overall survival rate was 97% recorded at 108 months. Forty-seven patients developed 58 second malignancies. The observed-to-expected ratio for second malignancies was 2.03 (95% confidence interval, 1.49 to 2.71). CONCLUSION: These results confirm previous observations that single courses of cladribine administered to patients with HCL induce high response rates, the majority of which are CRs. Most patients enjoy long-lasting complete remissions, and those patients who experience relapse can be successfully re-treated with cladribine.     

Low-dose interferon alfa-2b in the treatment of hairy cell leukemia

Twenty-two patients with hairy cell leukemia were treated with low-dose interferon alfa-2b (0.2 X 10(6) U/m2 given three times weekly) for 6-12 months. The overall response rate was 54%, with only 18% complete plus partial responses. The therapy had to be terminated early in five of these patients because their progressive disease led to severe cytopenia. Although the toxic effects with this regimen were minimal, the significantly lower response rate and the poorer quality of the responses prohibit its use as initial therapy in hairy cell leukemia.     

Platelet dysfunction in splenectomized patients with hairy cell leukemia

Platelet function was assessed in 17 patients with hairy cell leukemia who had undergone splenectomy. Defective PAF-induced aggregation and selective reduction of β-thromboglobulin were found in platelets from six and eight patients respectively. These defects were not necessarily associated with bleeding complications.     

Recombinant beta-serine-interferon in hairy cell leukemia compared prospectively with results with recombinant alpha-interferon

Ten patients with hairy cell leukemia (HCL) requiring therapy were treated with recombinant beta-serine-interferon (rIFN-beta ser) (90 x 10(6) units [U] subcutaneously three times a week). Eight patients were evaluable for response and nine for toxicity. Five patients (63%) showed normalization of peripheral blood counts, and an additional two patients (25%) showed improvement in at least one hematologic variable. Persistent hairy cells were detected in the bone marrow of all patients at the completion of therapy. All patients experienced influenza-like symptoms which were not dose limiting and which resolved with continued therapy. Erythema and induration at interferon injection sites developed in five patients (56%); one required dose reduction and another was removed from the study for this reason. Data from matched historical controls treated with recombinant alpha-interferon are presented for comparison. We conclude that rIFN-beta ser has activity in HCL.     

Pentostatin in the treatment of advanced hairy cell leukemia

2'-Deoxycoformycin (pentostatin [dCF]), a potent inhibitor of adenosine deaminase (ADA), was administered in a biweekly low-dose (2 to 4 mg/m2) intravenous (IV) schedule to patients with advanced hairy cell leukemia. Twenty-three patients were treated, including 12 patients previously treated by splenectomy and five patients treated with interferon. Twenty-one of 23 patients had objective responses, including 20 who achieved a complete remission (CR). Responses occurred rapidly, with an average time to CR of 5.4 months. Treatment was not continued once CR was achieved, and 15 of 20 patients remain in remission with an average duration of 12.6 months. CRs were achieved in both patients previously treated with interferon (three of five) and patients with marked splenomegaly (three of three). Relapses, when seen, have occurred in the bone marrow alone and the one patient who required retreatment was reinduced into CR. Toxicity has been mild and reversible, with nausea and vomiting, conjunctivitis, and skin rash as the main complications of treatment. dCF is the most effective single agent in the treatment of hairy cell leukemia, inducing a high percentage of CRs in all subgroups. Two multiinstitutional trials are now underway to compare its effectiveness v alpha interferon.     

Successful treatment of hairy cell leukemia variant with rituximab

Hairy cell leukemia (HCL) variant is a rare low-grade B-cell disorder affecting the elderly or middle-aged population with features intermediate between those of HCL and prolymphocytic leukemia. Unlike HCL, it is resistant to most conventional treatment. We report a case of a 53-year-old man who had refractory thrombocytopenia and lymphocytosis for 8 years. Investigations and analysis of spleen and bone marrow revealed a diagnosis of HCL variant. He opted for treatment with rituximab, a chimeric monoclonal antibody targeting CD20. There was complete recovery of his full blood count and a bone marrow biopsy performed 3 months post-treatment showed complete remission. This is, to our knowledge, the first reported patient with HCL variant for whom treatment with rituximab was successful, and this treatment needs further investigation.     

Immunotoxins in the treatment of refractory hairy cell leukemia

An increasing number of patients who have hairy cell leukemia (HCL) have persistent disease that requires treatment, despite purine analogs, splenectomy, interferon, and rituximab. Many of these patients have been treated successfully with immunotoxins. An immunotoxin contains a protein toxin connected to a cell-binding ligand, such as an antibody. An immunotoxin recognizes the target cell, internalizes, and the toxin translocates to the cytosol where it inhibits protein synthesis enzymatically. Immunotoxins that show activity in HCL contain truncated Psedomonas exotoxin fused to the Fv fragments of anti-CD25 or anti-CD22 monoclonal antibodies. Both agents, termed LMB-2 and BL22, respectively, have been tested in patients who have HCL after failure of purine analogs and other therapies; major responses have been achieved in most patients.     

Strategy for the treatment of hairy cell leukemia

Both splenectomy and alpha-interferon are efficient treatments for hairy cell leukemia. Since interferon therapy seems to induce remissions of the disease, avoids the risks of surgery, and sustains the spleen, it should be discussed if this therapy may replace splenectomy as primary treatment for this disease. In order to make this decision the biologic relevance of complete remissions in hairy cell leukemia, the reliability of methods to confirm remission, the benefits and risks of both splenectomy and interferon therapy, and some aspects of the pathogenesis of the disease have to be considered. Based on our experimental and clinical results and data from other groups, we conclude that splenectomy should still be recommended as primary therapy in hairy cell leukemia provided that treatment is indicated and the patient is eligible for surgery.     

Primary treatment of hairy cell leukemia with low-dose human recombinant interferon-alpha-2c (Hr-IFn alpha 2c) in comparison with therapy following splenectomy. Interferon (IFn-alpha 2c) in HCL before or after splenectomy

Within less than 14 months of recruitment 32 centers enrolled 97 patients in a multicenter trial for low-dose treatment of hairy cell leukemia (1.2 X 10(6) IU/m2 X 28 days s.c. with dose reduction according to clinically judged improvement) or ultra-low dose treatment (1.2 X 10(5) IU/m2, s.c. daily increasing to a well-tolerated dose) with Hr IFn-2c (arg). Induction therapy was limited to 84 days. Patients who reached the clinical stage Jansen I or A were then randomized to 2 arms either to receive further IFn (1.2 X 10(6) IU/m2 s.c.) twice a week or to be taken off treatment. For both arms induction therapy was reinstituted whenever a patient lost the criteria of Jansen stage A or I. The study included obligatory central diagnostic procedures and several special investigations. During the first year of the study a special problem evolved in the group of 34 patients with recurrent disease after splenectomy. Ten of them died, 9 of septicemia and 1 of bleeding complications, whereas only 1 death occurred in those patients who received IFn before splenectomy. The risk factors and the response to therapy in the two groups will be analyzed in order to define the criteria that will be needed for the proper choice of primary treatment for HCL. It appears important to us to restrict splenectomy to selected patients.     

毛细胞白血病的治疗新进展北大核心

毛细胞白血病(hairy cell leukemia,HCL)是一种罕见的B细胞肿瘤性疾病,主要是由BRAF V600E突变引起。常规的治疗药物是克拉屈滨、喷司他汀及干扰素,疗效显著,但50%的HCL患者仍会复发,急需新的药物来联合治疗。近年来,关于HCL的临床试验层出不穷,给HCL的治疗带来新的希望。因此,本文就HCL最新的治疗进展作一综述。     

An update: 12-year follow-up of patients with hairy cell leukemia following treatment with 2-chlorodeoxyadenosine.

Long-term results of both pretreated and previously untreated patients (pts) with hairy cell leukemia (HCL) using uniformly a single 7-day course of 2-chlorodeoxyadenosine (2-CdA) by continuous infusion are reported. In addition, the probability of obtaining another response with this drug in pts who relapsed after 2-CdA treatment will be addressed. A total of 44 consecutive pts (34 males, 10 females) with a median age of 57 years (range 33-77) at the time of initiation of 2-CdA treatment were analyzed. In all, 11 pts were pretreated with either splenectomy (n=6), interferon alpha (n=9) or deoxycoformycin (dCF) (n=3) or all procedures in sequence. Two pts treated with dCF did not respond to dCF, but only 2-CdA. The median time to the start of 2-CdA treatment of the 11 pretreated pts was 47 months (mo) (10-160). Out of 44, 43 (98%) achieved complete response (CR) (13 pts with residual disease-RD), one pt reached a good partial response with a single cycle of 2-CdA. Out of 44 pts, 13 had no nonhematologic toxicities at all. Toxicities (WHO grade I-IV) were mainly of grade I and II, in one pt grade IV infectious complication. Bone marrow biopsies were performed at the time of recovery of hematopoiesis, thereafter at 2-3 mo intervals, thereafter at 6 mo, and finally annually in 35 pts. The median follow-up is 8.5 years (0.1-12.2). Disease-free survival from the start of 2-CdA treatment is 36% at 12 years (median 8.4 years), 17/44 pts relapsed. Nine of these pts were treated with 2-CdA again, eight achieved a second CR (median 2.5 yrs), one pt did not respond. Eight of our cohort had a second malignancy before receiving 2-CdA. Six pts died in CR due to the second malignancy. The overall survival at 12 years after the start of 2-CdA treatment is 79%. 2-CdA is a safe and effective treatment of HCL inducing complete remissions in the majority of pts with only a single cycle of 2-CdA, and a paucity of toxicities. Responses are durable and long-lasting. Pts who relapsed following treatment with 2-CdA responded to subsequent retreatment with 2-CdA.