18例毛细胞白血病的临床分析

目的:探讨毛细胞白血病(HCL)的临床特点。方法:回顾性分析18例HCL患者的临床资料。结果:18例患者中,男13例,女5例,中位年龄51.5岁。腹胀是最常见主诉。初诊时脾大17例,肝大5例,淋巴结肿大6例。白细胞数增高6例,减低7例,正常5例。TRAP阳性15例,阴性3例。网状纤维增多3例,板层复合体(RLC)14例中存在1例,细胞遗传学改变7例中存在2例。11例单用干扰素治疗,8例有效,3例无效中2例行脾切除仍有效。干扰素联合脾切除3例有效。结论:HCL患者肝脾淋巴结肿大易见,网状纤维增多不多见,RLC少见,部分有细胞遗传学异常,干扰素联合脾切除是治疗的有效方法。     

18例毛细胞白血病的临床分析

目的探讨毛细胞白血病(HCL)的临床特点.方法回顾性分析18例HCL患者的临床资料.结果18例患者中,男13例,女5例,中位年龄51.5岁.腹胀是最常见主诉.初诊时脾大17例,肝大5例,淋巴结肿大6例.白细胞数增高6例,减低7例,正常5例.TRAP阳性15例, 阴性3例.网状纤维增多3例,板层复合体(RLC)14例中存在1例, 细胞遗传学改变7例中存在2例.11例单用干扰素治疗, 8例有效,3例无效中2例行脾切除仍有效.干扰素联合脾切除3例有效.结论HCL患者肝脾淋巴结肿大易见, 网状纤维增多不多见, RLC少见, 部分有细胞遗传学异常,干扰素联合脾切除是治疗的有效方法.     

CD52 expression in hairy cell leukemia

Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder characterized by splenomegaly, pancytopenia, and circulating atypical lymphocytes with circumferential cytoplasmic projections. Although uncommon, HCL cases refractory to standard therapy occur, and effective alternatives are limited. There is evolving literature supporting monoclonal antibody therapy in the treatment of B-cell lymphoid malignancies, including anti-CD52 (Campath-1H, alemtuzumab). We have examined nine cases of HCL and one case of HCL variant by flow cytometry for CD52 expression. All cases expressed CD52 antigen in 92-100% of the malignant cells. The demonstration of CD52 antigen expression on HCL cells provides the rationale for the use of alemtuzumab in refractory HCL.     

Deoxycoformycin-induced immunosuppression in patients with hairy cell leukemia

Immune function in patients with hairy cell leukemia (HCL) was examined serially during treatment with alternating monthly cycles of recombinant interferon alpha-2a and 2'-deoxycoformycin (dCF). At presentation, most patients had normal numbers of T lymphocytes and their cells had normal proliferative responses to mitogens [phytohemagglutinin (PHA) and concanavalin A (Con A)] and alloantigens. Patients had severe monocytopenia, decreased delayed-type hypersensitivity (DTH) reactions, and decreased peripheral blood natural killer (NK) activity. Treatment caused a profound decrease in all lymphocyte subpopulations. T cells were more affected than B cells or NK cells. Numbers of CD4+ and CD8+ lymphocytes decreased to levels less than 200 cells/microliters in all patients during treatment. This decrease in T cell number was associated with a marked decrease in proliferative responsiveness to PHA, Con A, and alloantigens. These abnormalities persisted throughout the 14 months of treatment and have continued for up to 6 months beyond discontinuation of treatment. NK cell activity increased during treatment, but cycled depending on the phase of treatment; highest activities were observed after interferon (IFN)-alpha and lower levels of activity were observed after dCF. DTH responses generally did not improve during therapy. Levels of IgM, IgG, IgA, and IgD did not change during treatment, but IgE levels rose in most patients. All immunosuppressive effects were attributable to dCF since patients receiving IFN-alpha 2a alone did not exhibit these same immunosuppressive effects, and patients receiving dCF alone after IFN failure exhibited similar abnormalities. Despite this severe immunosuppression from dCF, life-threatening opportunistic infections have not been observed in our patient population. Six patients developed localized Herpes zoster infection among 21 patients who had received dCF. Pending the results of long-term follow-up, we recommend that dCF be reserved for patients who have failed splenectomy and IFN therapy.     

Clinico-biological implications of increased serum levels of interleukin-8 in B-cell chronic lymphocytic leukemia

BACKGROUND AND OBJECTIVE: Constitutive cellular expression and serum release of biologically active interleukin-8 (IL-8) has been reported in B-cell chronic lymphocytic leukemia (CLL). Given the autocrine role played by IL-8 in the process of cell accumulation characteristic of this disease we tried to investigate clinico-biological implications of increased serum levels of this cytokine in an unselected series of B-cell CLL patients. DESIGN AND METHODS: Serum levels of IL-8 were determined at the time of diagnosis in 58 previously untreated B-CLL patients using an immunoenzyme assay. Results were correlated with main clinico-hematologic features as well as with the risk of disease progression. Finally, we looked for associations between IL-8 and molecules directly involved in apoptosis, such as intracellular bcl-2 and soluble APO-1/Fas. RESULTS: Increased serum levels of IL-8 were found in 15 out of 58 (25.8%) B-cell CLL patients. Serum levels of IL-8 did not reflect clinico-biological features representative of tumor mass such as clinical stage, histopathologic pattern of bone marrow (BM) involvement, b2-microglobulin, sCD23 and sCD27 titers. Interestingly, circulating levels of IL-8 paralleled those of intracellular bcl-2 (r = 0.522; p = 0.01), thus confirming that the antiapoptotic effect of IL-8 can be exerted through a bcl-2 dependent pathway. Levels of IL-8 did not match those of soluble Apo-1/Fas (r = -0.013; p = 0.943). Finally, stage A patients with levels of IL-8 above the median value (i.e. 4.5 pg/mL) were more likely to progress to a more advanced clinical stage than those with levels below the median value (p < 0.05). INTERPRETATION AND CONCLUSIONS: IL-8 is an interesting marker in B-cell CLL, closely involved in the pathogenesis of disease. Furthermore, it is useful for predicting the pace of disease progression in early clinical stages.     

Surface immunoglobulins on hairy cells of 55 patients with hairy cell leukemia

Surface immunoglobulins (SIg) were determined on peripheral blood samples from 55 patients with hairy cell leukemia (HCL) and on hairy cells from spleen preparations of 14 of these 55 patients. The patterns of SIg for HCL was compared to the patterns on peripheral blood leukemic cells from 39 patients with chronic lymphocytic leukemia (CLL) and 15 patients with poorly differentiated lymphocytic (PDL) lymphoma. Of the 55 HCL patients, 42 could be scored for individual heavy and light chains; 16 had only IgG, 14 had two or three heavy chains, 7 had only IgD, and 5 cases had no SIg and were E-rosette negative. This pattern was different from the B-cell pattern in CLL and PDL where there were few cases of IgG alone (5%) and many cases of IgM alone (50%). Surface marker profile did not correlate with survival in any of the sub-groups tested. HCL appears to be a B-cell lymphoproliferative disease in greater than 90% of cases; many combinations of heavy chains with only a single light chain can be demonstrated.     

Disseminated atypical mycobacterial infection in patients with hairy cell leukemia

Disseminated atypical mycobacterial infections developed in nine of 186 patients with hairy cell leukemia who were seen over 10 years at the University of Chicago Hospital. Clinically, these patients had symptoms of fever and chills; an infiltrate was usually present on chest radiography. Invasive diagnostic studies, including thoracotomy and laparotomy, were necessary for confirmation of the diagnosis of atypical mycobacteria infection. Confirmatory culture specimens were obtained from lymph nodes, liver, and splenic tissue. Six patients had infections with Mycobacterium kansasii; two with M. avium-intracellulare; and one with M. chelonei. Treatment with multiple anti-tuberculosis drugs was initiated either empirically (six patients); after obtaining pathologic evidence of granuloma or acid-fast bacilli (two patients); or after obtaining a positive culture result (one patient). Five of the nine patients survived the infection and continued taking anti-tuberculosis drugs for total periods of nine months to two years. Awareness of the association between hairy cell leukemia and atypical mycobacteria infection, with early consideration of invasive diagnostic studies, as well as empiric anti-tuberculosis therapy, may prolong the survival time for many patients with hairy cell leukemia.     

Serum levels of CD8 antigen and soluble interleukin 2 receptors in patients with B cell chronic lymphocytic leukemia

We assayed the plasma levels of CD8 antigen (CD8Ag) and soluble interleukin 2 receptor (sIL-2R) in 34 subjects with B cell chronic lymphocytic leukemia (B-CLL) and in 15 controls using an immunoenzymatic method. The results showed higher average levels of soluble CD8 (sCD8) and sIL-2R in the leukemic patients compared to the controls (sCD8 = 860 vs. 306 U/ml; sIL-2R = 4,131 vs. 311 U/ml). The two antigen levels were significantly higher in patients with progressive disease than in those with indolent disease, and they also correlated with Rai's stage. sIL-2R levels correlated with lymphocyte count (p less than 0.001), while there was no correlation between sCD8 levels and total number of lymphocytes. These results seem to show that the measurement of serum levels of CD8Ag and sIL-2R may be a useful tool in the prognostic evaluation of patients with B-CLL.     

40例毛细胞白血病临床特征分析

目的:研究我国毛细胞白血病(HCL)的临床及实验室检查特点。方法:回顾性总结40例HCL患者的临床及相关实验室检查资料。结果:①脾大是HCL的最主要的症状体征,而全血细胞减少者比例较少,在经典型中也仅占1/3左右;变异型白细胞计数常增高;②电镜检查核糖体-板层复合物的阳性率仅有20%～30%;③多色流式细胞学表型分析发现典型的毛细胞表达CD19、CD20、CD22、CD25、CD103、CD11c和sIgM,是诊断的重要依据;④核苷类似物治疗HCL疗效优于其他治疗,值得推荐;⑤变异型HCL比例较高,表现不典型,且治疗效果差。结论:我国HCL中全血细胞减少者比例较低,电镜核糖体-板层复合物的阳性率低,而毛细胞免疫表型与国外类似,核苷类似物治疗效果也较好。变异型HCL比例高于国外,治疗反应差。     

Intensive chemotherapy of hairy cell leukemia in patients with aggressive disease

Seven patients with hairy cell leukemia were treated by intensive chemotherapy because they were considered to have a progressive disease and a poor short-term prognosis. The mean age was 47 years (range, 36 to 58). Six of seven patients had prior splenectomies with minor or transient hematologic responses. One patient had no spleen enlargement. The seven patients had never received any cytotoxic drugs and had prolonged granulocytopenia (less than 300/microL) with recurrent, severe infectious episodes. Chemotherapy included Rubidazone (zorubicine hydrochloride) 450 mg/m2 on day 1, arabinosyl cytosine 200 mg/m2/d from day 1 to day 5, and cyclophosphamide, 2,000 mg/m2 on day 5. Responses were assessed through examination of repeat bone marrow biopsy specimens and blood counts. A complete response was defined as normal blood counts associated with the disappearance of hairy cell infiltration and fibrosis on the bone marrow biopsy specimens. A partial response was defined as normal blood counts with persistence of leukemic cells in the bone marrow. Three patients achieved a complete response, and one patient had a partial response. Three patients died of infectious complications during induction chemotherapy. For the responding patients, the mean duration of aplasia was 37 +/- 5 days. Follow-up for the responding patients has been 44+, 24, 32+, and 23+ months. One patient with a complete response died while on maintenance therapy. We conclude that complete and prolonged histologic remission of hairy cell leukemia can be obtained with intensive chemotherapy. The toxicity of chemotherapy is such, however, that progressive disease after splenectomy needs to be more clearly defined.     

Filgrastim for cladribine-induced neutropenic fever in patients with hairy cell leukemia

Cladribine treatment of hairy cell leukemia (HCL) is complicated by neutropenic fever in 42% of patients despite documented infections being relatively uncommon. We performed a study of priming filgrastim followed by cladribine and then filgrastim again to determine if filgrastim would lead to a reduction of neutropenia and febrile episodes. Thirty-five patients received filgrastim and cladribine and were compared with 105 historic controls treated with cladribine alone. Cladribine was administered at 0.1 mg/kg/d by continuous infusion for 7 days. Filgrastim was administered at 5 micrograms/kg/d subcutaneously on days -3, -2, and -1 and then again after the completion of cladribine until the absolute neutrophil count (ANC) was >/=2 x 10(9)/L on 2 consecutive days (days +8, +9, etc). After filgrastim priming, the median ANC increased from 0.9 x 10(9)/L to 2.26 x 10(9)/L (2.5-fold increase), and after cladribine, the median nadir ANC in the filgrastim-treated group was 0.53 x 10(9)/L compared with 0.29 x 10(9)/L among historic controls (P =. 04). The median number of days to an ANC greater than 1.0 x 10(9)/L was 9 days in the filgrastim-treated group versus 22 days among historic controls (P < 10(-5)). The percentage of febrile patients, number of febrile days, and frequency of admissions for antibiotics were not statistically different in the two groups. Filgrastim regularly increases the ANC in patients with HCL and shortens the duration of severe neutropenia after cladribine. This phase II study, with comparison to historical controls, failed to detect any clinical advantage from the use of filgrastim and cladribine in the treatment of HCL. Accordingly, the routine adjunctive use of filgrastim with cladribine in the treatment of HCL cannot be recommended.     

Long-term follow-up of hairy cell leukemia patients treated with 2-chlorodeoxyadenosine

BACKGROUND AND OBJECTIVES: The management of patients with hairy cell leukemia (HCL) has evolved significantly over the past two decades. In fact, both 2'-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (2-CdA) induce complete response (CR) in the majority of the patients with HCL. However, fewer data exist on the long-term follow-up of patients who have undergone the characteristically brief exposure to 2-CdA therapy. Thus, it is important to evaluate such long-term outcome data in order to increase understanding of the efficacy of this agent in the management of HCL. DESIGN AND METHODS: We reviewed the long-term follow-up data of 23 HCL patients pretreated with a-interferon and then treated with 2-CdA administered as a single continuous IV infusion for 7 days at the dose of 0.1 mg/kg/day in our institute between January 1991 and February 1992. RESULTS: Of 23 patients, 19 (83%) achieved a CR and 4 (17%) a partial response (PR), with an overall response rate of 100%. After a median follow-up of 102 months (range: 96-108), there have been 9 (39%) relapses. In the PR subset 100% of patients relapsed within the first 45 months of follow-up. In the group of patients who obtained a CR, 26% relapsed; all these relapses occurred between 54 and 86 months. Overall, the median time to relapse was 54 months (range: 16-86). All relapsed patients were re-treated with 2-CdA at the dose of 0.15 mg/kg/day for 5 days in a 2-hour infusion, and 67% and 22% then obtained CR or PR, respectively. The median duration of this second response was 48 months (range: 22-80). All but one of these patients are still maintaining the second response to 2-CdA. The 9-year overall and the relapse-free survivals are 91% and 70%, respectively. INTERPRETATION AND CONCLUSIONS: In HCL patients a single dose of 2-CdA induces a long-term CR with a 9-year survival > 90%. Over 50% of patients appear to be clinically cured by this procedure, but the lack of a long-term plateau in the relapse-free survival curve means caution on this point is still warranted.     

Soluble CD22 as a tumor marker for hairy cell leukemia

CD22 is an important immunotherapeutic target on B-cell malignancies, particularly hairy cell leukemia (HCL), but its soluble extracellular domain, sCD22, has not yet been reported in the blood. By immunoaffinity and enzyme-linked immunosorbent assay techniques using anti-CD22 monoclonal antibodies, we identified the 100-kDa extracellular domain of CD22 and an 80-kDa processed form in serum of patients with HCL. The median sCD22 level measured by enzyme-linked immunosorbent assay was 18 ng/mL for 93 patients with HCL. sCD22 levels varied from 2.1 to 163 ng/mL and were higher (P < .001) than 23 normal donors (median, 0.6 ng/mL). More than 95% of normal donors had sCD22 levels less than 1.9 ng/mL. sCD22 levels were proportional to concentrations of circulating HCL cells (P = .002), and HCL spleen size (P < .001). sCD22 levels normalized with complete but not partial response to treatment. sCD22 levels up to 300 ng/mL had less than a 2-fold effect on the cytotoxicity of the anti-CD22 recombinant immunotoxin BL22. sCD22 levels may be useful to follow in patients with HCL and may be more specific than sCD25 in patients with CD22(+)/CD25(-) disease. Trials are listed on www.cancer.gov as NCT00002765, NCT00021983, NCT00074048, NCT00085085, NCT00337311, and NCT00462189.     

Effective natural interferon-alpha therapy in recombinant interferon-alpha-resistant patients with hairy cell leukemia

To explore the relationship between anti-interferon-alpha (anti-IFN-alpha) antibodies and loss of clinical responsiveness to IFN-alpha treatment, we examined sera from 59 patients with hairy cell leukemia who responded to therapy with recombinant IFN-alpha-2a (rIFN-alpha-2a). During the first 2 years of therapy, 10 patients developed rIFN-alpha-2a-neutralizing and 15 rIFN-alpha-2a-binding antibodies. Nine of the 59 initially responding patients became resistant to rIFN-alpha-2a and suffered a relapse of the disease at 7 to 24 months of treatment. All nine relapsing patients tested positive for both neutralizing and binding antibodies with titers above 400 INU/mL, while none of the antibody-negative patients relapsed. Six patients with detectable binding antibody titers below 400 INU/mL continued to respond to treatment. By measuring the IFN kinetics and the levels of the IFN-induced Mx-homologous protein in mononuclear cells after a single injection each of rIFN-alpha-2a and nIFN-alpha the IFN antibodies of eight of the nine resistant rIFN-alpha patients were found to be highly specific for rIFN-alpha-2a. Therefore, these eight patients were switched to natural IFN-alpha (nIFN-alpha) therapy at doses of 3 million IU, three times a week. All eight patients responded to treatment with nIFN-alpha, achieving durable objective responses similar to those obtained previously with rIFN-alpha-2a. These data clearly demonstrate that rIFN-alpha antibody-positive patients can effectively be treated with nIFN-alpha.     

Alpha-interferon activates the natural killer system in patients with hairy cell leukemia

To elucidate the mechanisms of alpha-interferon's (alpha-INF) therapeutic effect on clinical and laboratory findings in hairy cell leukemia, we sequentially monitored different immunologic parameters in three patients treated with recombinant alpha-INF. The most evident effect of this treatment on the immune system was the recovery of natural killer (NK) cell in vitro activity of peripheral blood lymphocytes, which was severely impaired before therapy. In particular, NK function began to improve after 3 months, and a complete recovery was obtained after 6 months in all cases. This increase parallels the improvement in clinical and laboratory findings.     

Adult T cell leukemia with CD4- and CD8-

A 53-year-old woman born in Kamo village of Shizuoka prefecture was admitted to Juntendo Izunagaoka hospital complaining cough and appetite loss. On physical examinations, general lymphadenopathy and hepatosplenomegaly were recognized. And also dry rales and wet rales were heard in the bilateral lungs. On hematological examinations, leukocytes has counted 74,900/microliters, of which 61% atypical lymphocytes, and there were HTLV-I infection and positive anti-ATLA antibody. By the above results, she was diagnosed as adult T cell leukemia (ATL). T cell subset analysis was (CD4-, CD8-, CD3-), which is rare in ATL. Three months after the admission, she was died of disturbances of respiratory function in spite of VEPA therapy. Surface marker changed from CD3- to CD3+ in the course. To illuminate this mechanism will be a key step for the future study.