含氟达拉滨的联合化疗方案治疗慢性淋巴细胞白血病／小淋巴细胞性淋巴瘤

目的：评价以氟达拉滨为主的化疗方案治疗慢性淋巴细胞白血病／小淋巴细胞淋巴瘤（CLI／SLL）的疗效和不良反应。方法：采用氟达拉滨为主的化疗方案，FC方案：氟达拉滨＋环磷酰胺；FMD方案：氟达拉滨＋米托蒽醌＋地塞米松；FMC方案：氟达拉滨＋米托蒽醌＋环磷酰胺，共治疗18例CLL／SLL患者，其中初发9例，复发、难治9例。结果：18例患者平均完成4．2个周期，完全缓解（CR）率61．1％，部分缓解（PR）率22．2％，总的有效（OR）率83．3％。初发组CR率66．7％。PR率33．3％，OR率100％；复发、难治组CR率55．6％，PR率11．1％，OR率66．7％，两组CR、OR率无显著性差异（P〉0．05）。FC方案和FMD方案治疗组CR、OR率无显著性差异（P〉0．05）。主要不良反应为骨髓抑制和免疫功能抑制，27．8％的患者出现Ⅲ～Ⅳ级粒细胞减少，22．2％的患者出现Ⅲ～Ⅳ级血小板减少。5例患者出现感染、发热，其中1例死亡。其它毒性包括恶心、呕吐，轻度肝肾功能损害，自身免疫性溶血性贫血。中位随访时间24月（1～40月），2年生存率88．9％，2年PFS率81．8％。初发组2年生存率100％，2年PFS率100％；难治组2年生存率83．3％，2年PFS率66．7％，两组无显著性差异（P〉0．05）。结论：氟达拉滨为主的联合化疗方案对CIL／SLL疗效好，同时患者对其耐受性亦较佳。     

U.S. Food and drug administration approval: rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with chronic lymphocytic leukemia

Purpose.

To describe the clinical studies that led to the FDA approval of rituximab in combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with chronic lymphocytic leukemia (CLL).

Materials and Methods.

The results of two multinational, randomized trials in CLL patients comparing rituximab combined with fludarabine and cyclophosphamide versus FC were reviewed. The primary endpoint of both studies was progression-free survival (PFS).

Results.

The addition of rituximab to FC decreased the risk of a PFS event by 44% in 817 previously untreated patients and by 24% in 552 previously treated patients. Median survival times could not be estimated. Exploratory analysis in patients older than 70 suggested that there was no benefit to patients when rituximab was added to FC. The safety profile observed in both trials was consistent with the known toxicity profile of rituximab, FC, or CLL.

Conclusions.

On the basis of the demonstration of clinically meaningful prolongation of PFS, the FDA granted regular approval to rituximab in combination with FC for the treatment of patients with CLL. The magnitude of the treatment effect in patients 70 years and older is uncertain.     

Chemoimmunotherapy with oral low-dose fludarabine,cyclophosphamide and rituximab (old-FCR) as treatment for elderly patients with chronic lymphocytic leukaemia

Median age at diagnosis for chronic lymphocytic leukaemia (CLL) patients is now 72 years, thus a consistent number of patients may not tolerate standard doses i.v. of fludarabine, cyclophosphamide and rituximab (FCR), the best available therapy, due to unacceptable myelotoxicity and risk of severe infections. We studied safety and efficacy of the addition of rituximab to the oral low-dose FC regimen (old-FCR) in a selected population of 30 elderly (median age 75, 15 untreated, 15 treated with 1 prior therapy) CLL patients. Complete remission (CR) rate was 80% in the untreated patients (overall response rate, ORR 93%), and 30% in pretreated patients (ORR 74%). Progression free survivals (PFS) were 45 months and 30 months in the untreated and treated patients, respectively. In patients achieving CR, old-FCR led to PFS of 67 months. Moreover, haematological toxicity was mild (grade 3–4: 15%) and patients were treated mostly in outpatient clinic. Old-FCR could be a good therapy option for elderly CLL patients outside clinical trials, larger studies are needed to confirm our findings.     

Accelerated growth of skin carcinoma following fludarabine therapy for chronic lymphocytic leukemia

We present four patients with chronic lymphocytic leukemia treated with fludarabine, who developed aggressive skin cancer after years of quiescence, a short time after institution of treatment. Their leukemias responded well to therapy with fludarabine with initial treatment as well as relapse. Three patients had recurrence with basal cell carcinomas with multiple, rapidly growing tumors and one had recurrence of both basal and squamous cancers and eventually died of metastatic squamous cell carcinoma. Fludarabine induces prolonged period of lymphopenia, affecting especially the T cell population, which is crucial in the defense against skin cancers. There appears to be a direct association between fludarabine and the flare up of skin cancers in these patients, possibly analogous to the increased incidence of these malignancies in patients on chronic cyclosporine immunosuppression.     

Fludarabine plus alemtuzumab (FA) front-line treatment in young patients with chronic lymphocytic leukemia (CLL) and an adverse biologic profile

In 45, ≤60 years old patients with CLL and an adverse biologic profile, a front-line treatment with Fludarabine and Campath (Alemtuzumab^®) was given. The overall response rate was 75.5%, the complete response rate (CR) 24.4% with the lowest CR rates, 16.7% and 8.3%, in 11q and 17p deleted cases. The 3-year progression-free survival (PFS) and overall survival were 42.5% and 79.9%, respectively. PFS was significantly influenced by CLL duration, beta2-microglobulin, and improved by post-remissional stem cell transplantation. Front-line fludarabine and alemtuzumab showed a manageable safety profile and evidence of a benefit in a small series of CLL patients with adverse biologic features.     

Incidence of second neoplasia in patients with B-cell chronic lymphocytic leukemia treated with chlorambucil maintenance chemotherapy

The aim of this retrospective study was to examine the impact of prolonged chlorambucil (CLB) therapy on the development of second neoplasia (SN) in 389 patients with B-CLL, comparing untreated cases with those receiving CLB as induction plus maintenance therapy. Fifty-nine SN cases were observed (15.1%) at a median follow-up of 79 months. SN occurrence was significantly related to Binet stage. No difference was detected between untreated and CLB treated cases neither in terms of SN incidence (12.2% vs 18.1%) nor in the median follow-up (81 vs 79.1 months). Moreover, SN free survival was not different between these two groups. Four out of 13 CLB treated patients (30.8%) developed s-MDS after a subsequent treatment with fludarabine plus cyclophosphamide (F + C). In conclusion, SN development is dependent on the length of follow-up rather than on therapy duration. F + C should be administered with caution after prolonged CLB therapy.     

Prognostic significance of serum immunoglobulin paraprotein in patients with chronic lymphocytic leukemia

The aim of this study was to explore the clinical and other associated laboratory features of chronic lymphocytic leukemia (CLL) patients with immunoglobulin (Ig) paraproteinemia. Serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) were performed to measure serum Ig paraprotein. The correlations between serum Ig paraprotein and other prognostic factors were analyzed. Univariate and multivariate Cox regression analyses were used to assess associations between survival time and potential risk factors. In 133 Chinese CLL patients, 27 (20.3%) patients occurred Ig paraproteinemia at diagnosis. According to the correlation analysis, advanced Binet stage (r = 0.314, P < 0.001), direct antiglobulin test (DAT)-positive (r = 0.366, P < 0.001), high level of serum β2-microglobulin (β2-MG) (r = 0.296, P = 0.001) and thymidine kinase (TK) 1 (r = 0.227, P = 0.037), unmutated immunoglobulin heavy chain variable gene (IGHV) status (r = 0.284, P = 0.002), ZAP-70-positive (r = 0.305, P = 0.001), CD38-positive (r = 0.284, P = 0.002), and cytogenetic abnormalities of del(17p13) or del(11q22.3) (r = 0.208, P = 0.032) emerged as factors significantly related to the occurrence of Ig paraproteinemia. Survival analysis showed that the patients with Ig paraproteinemia had significantly shorter survival times than the patients without serum Ig paraprotein (P = 0.013). Binet stage (P = 0.028), high levels of lactate dehydrogenase (LDH) (P = 0.004), IgG paraproteinemia (P = 0.048), IgM paraproteinemia (P = 0.001), ZAP-70-positive (P = 0.003), DAT-positive (P = 0.013), unmutated IGHV status (P = 0.009), and del(17p13) (P = 0.001) were the adverse factors in determining overall survival (OS). Del(17p13) (P = 0.006), ZAP-70 (P = 0.030), and IgM paraproteinemia (P = 0.040) were the variables strongly associated with OS by multivariate Cox regression analysis. It was showed that serum Ig paraprotein might be applied for the assessment of prognosis in patients with CLL.     

急性髓系白血病合并慢性淋巴细胞白血病一例报道及文献复习

 目的 探讨急性髓系白血病（AML）合并慢性淋巴细胞白血病（CLL）的临床特点、病因、诊断、治疗及预后。方法 临床诊断1例AML合并CLL,并就相关文献进行复习。结果 患者经MA方案（米托蒽醌10 mg／d第1 ~ 3天,阿糖胞苷150 mg／d第1,3,5,7天,200 mg第2,4,6天）化疗后取得完全缓解,但CD19阳性的淋巴细胞（表达CD20,CD23,SIgM,部分表达CD5,CD22,CD25）仍然存在,于9个月后AML复发未能再次缓解而死亡。结论 AML合并CLL为一种具有特殊生物学特征的罕见疾病,免疫分型和细胞遗传学技术在疾病的诊断和认识中发挥重要作用,治疗应以AML为主。     

Idiopathic thrombocytopenic purpura and myasthenia gravis after fludarabine treatment for chronic lymphocytic leukemia

We report a patient with chronic lymphocytic leukemia (CLL) who developed idiopathic thrombocytopenic purpura (ITP) and myasthenia gravis (MG) after fludarabine therapy. ITP developed after 6 cycles of fludarabine treatment, and MG occurred 2 months after the onset of ITP. MG was successfully treated with immunosuppressive therapy and plasma exchange, while rituximab was effective for CLL and ITP. Fludarabine seemed to have an important role in the onset of ITP and MG in this case.     

Combined fludarabine and rituximab for low grade lymphoma and chronic lymphocytic leukemia

As both fludarabine and rituximab are active against indolent lymphoproliferative disorders, we have studied the combination of fludarabine and rituximab in patients with low-grade lymphoma and chronic lymphocytic leukemia (CLL) in phase I/II fashion. Of 33 patients enrolled, 21(63.6%) had low-grade lymphoma and 12 (36.4%) had CLL. They received fludarabine 30 mg/m 2 on days 1-4 and rituximab 125, 250 or 375 mg/m 2 on day 5 at intervals of 28 days to a maximum of 8 cycles. Three patients were removed from the study because of rituximab-associated anaphylaxis and four because of prolonged hematopoietic toxicity. Toxicity and responsiveness did not differ at the different dose levels of rituximab. For 29 evaluable patients, responses were seen in 82.8% and complete responses in 34.5%. Of 7 responding patients not referred for stem cell transplantation, 6 remain in complete remission at a median follow-up of 16 months (range 4-30 months). Of 13 previously untreated patients, all responded and 46.2% had a complete response. Of 16 previously treated patients, 68.5% responded and 25% had a complete response. The combination of fludarabine and rituximab has major activity and acceptable toxicity in patients with low-grade lymphoma and CLL.     

Recent advances in chronic lymphocytic leukemia

Chronic lymphocytic leukemia is a low-grade B-lineage lymphoid malignancy. Based on recent findings, the disease appears to be more heterogeneous than previously thought. Many cases may require no treatment at all unless patients become symptomatic or develop signs of rapid progression. Even in this setting, treatment is noncurative and is directed at reducing the symptoms. Recently described molecular risk features may help delineate at initial diagnosis which patients will have a more aggressive course. Newer treatment regimens incorporating purine nucleoside analogs and monoclonal antibodies have increased the rate of molecular complete remissions, which may lead to increased survival. Reduced intensity conditioning regimens have made the potentially curative modality of allogeneic transplantation more widely available. All of these recent treatments have significant risks of infectious complications, which must be carefully weighed against the risks posed by the underlying disease, and many low-risk asymptomatic patients do not require any treatment. A proposed risk-based treatment algorithm will be discussed.     

Acute myeloid leukemia and lung cancer occurring in a chronic lymphocytic leukemia patient treated with fludarabine and autologous peripheral blood stem-cell transplantation

An increased incidence of different malignancies associated to chroniclymphocytic leukemia (CLL) has been reported. The association of CLL and acuteleukemia is a rare event described in <1% of CLL, the type of acuteleukemia being either from the lymphoid or more often from the myeloidlineage. The coexistence of acute myeloid leukemia (AML) and CLL in the samepatient has been occasionally reported. Most of these cases have beenassociated with the administration of chemotherapy or radioterapy for CLL,suggesting that the former may be a secondary leukemia. On the other hand, CLLcould precede, but could also be diagnosed at the same, or delayed time asAML, suggesting the presence of other leukemogenic factors. We describe theexceptional development of AML and lung cancer in a patient with previouslydiagnosed CLL in minimal residual disease status after fludarabine treatmentfollowed by autologous peripheral blood stem-cell transplantation.     

A novel phenotypic method to determine fludarabine triphosphate accumulation in T-lymphocytes from hematopoietic cell transplantation patients

Purpose  Fludarabine is an integral anticancer agent for patients with chronic lymphocytic leukemia (CLL) and those receiving conditioning regimens prior to allogeneic hematopoietic cell transplantation (HCT). An individual’s response to fludarabine may be influenced by the amount of CD4⁺ and CD8⁺ T-lymphocyte suppression. Fludarabine undergoes cellular uptake and activation to form the cytotoxic metabolite, fludarabine triphosphate (F-ara-ATP). Methods  We have previously developed a highly sensitive LC–MS method to quantitate intracellular F-ara-ATP concentrations in a leukemic cell line. However, quantitation of F-ara-ATP concentrations within CD4⁺ and CD8⁺ T-lymphocytes from pharmacokinetic blood samples obtained from patients receiving fludarabine therapy is not feasible because of the limited number of T-lymphocytes that can be isolated from each blood sample. Thus, we sought to determine F-ara-ATP accumulation after ex vivo exposure of freshly isolated human CD4⁺ or CD8⁺ T-lymphocytes to fludarabine. The method was optimized in T-lymphocytes obtained from healthy volunteers, and proved to be a feasible method to determine F-ara-ATP accumulation in patients undergoing HCT. Results  Considerable variability was observed in F-ara-ATP accumulation in HCT patients (10.5- and 12.5-fold in CD4⁺ and CD8⁺ cells, respectively), compared to healthy volunteers (1.6- and 1.9-fold in CD4⁺ and CD8⁺ cells, respectively). Larger variability was also observed in gene expression of transporters and enzymes involved in F-ara-ATP accumulation in HCT patients; however, F-ara-ATP accumulation was not correlated with gene expression, which is in agreement with previous studies. Conclusions  The quantitation of F-ara-ATP accumulation in T-lymphocytes provides a novel tool to evaluate patient sensitivity to fludarabine. This tool can be used in future studies to evaluate whether intracellular F-ara-ATP accumulation is associated with efficacy and/or toxicity in patients receiving fludarabine.     

Intracellular disposition of fludarabine triphosphate in human natural killer cells

Purpose  Fludarabine is a key component of several reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Shortly after reduced-intensity conditioning, the percent of donor natural killer (NK) cells has been associated with progression-free survival. Insufficient suppression of the recipient’s NK cells by fludarabine may lead to lower donor chimerism; however, the effect of fludarabine upon NK cells is poorly understood. Thus, in purified human NK cells we evaluated the uptake and activation of fludarabine to its active metabolite, fludarabine triphosphate (F-ara-ATP), and assessed the degree of interindividual variability in F-ara-ATP accumulation. Methods  Intracellular F-ara-ATP was measured in purified NK cells isolated from healthy volunteers (n = 6) after ex vivo exposure to fludarabine. Gene expression levels of the relevant transporters and enzymes involved in fludarabine uptake and activation were also measured in these cells. Results  F-ara-ATP accumulation (mean ± SD) was 6.00 ± 3.67 pmol/1 × 10⁶ cells/4 h, comparable to average levels previously observed in CD4⁺ and CD8⁺ T-lymphocytes. We observed considerable variability in F-ara-ATP accumulation and mRNA expression of transporters and enzymes relevant to F-ara-ATP accumulation in NK cells from different healthy volunteers. Conclusions  Human NK cells have the ability to form F-ara-ATP intracellularly and large interindividual variability was observed in healthy volunteers. Further studies are needed to evaluate whether F-ara-ATP accumulation in NK cells are associated with apoptosis and clinical outcomes.     

Gene mutations in chronic lymphocytic leukemia

The recent discovery of genes mutated in chronic lymphocytic leukemia (CLL) has stimulated new research into the role of these genes in CLL pathogenesis. CLL cases carry approximately 5–20 mutated genes per exome, a lower number than detected in many human tumors. Of the recurrently mutated genes in CLL, all are mutated in 10% or less of patients when assayed in unselected CLL cohorts at diagnosis. Mutations in TP53 are of major clinical relevance, are often associated with del17p and gain in frequency over time. TP53 mutated and associated del17p states substantially lower response rates, remission duration, and survival in CLL. Mutations in NOTCH1 and SF3B1 are recurrent, often associated with progressive CLL that is also IgV_H unmutated and ZAP70-positive and are under investigation as targets for novel therapies and as factors influencing CLL outcome. There are an estimated 20–50 additional mutated genes with frequencies of 1%–5% in CLL; more work is needed to identify these and to study their significance. Finally, of the major biological aberration categories influencing CLL as a disease, gene mutations will need to be placed into context with regard to their ultimate role and importance. Such calibrated appreciation necessitates studies incorporating multiple CLL driver aberrations into biological and clinical analyses.     

The ultrastructural study of non-Hodgkin’s lymphoma cell,chronic lymphocytic and hairy cell leukemia

Non-Hodgkin’s lymphoma cell leukemia (NHLCL), chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HLC) are the diseases very similar to each other. The differential diagnosis is very difficult, especially when there are small lymphoid cells in peripheral blood and bone marrow under light microscope. We have observed 34 cases with electron microscope. The studies were correlated with clinical manifestation, cytology, pathology and immunologic histochemistry. Ultrastructural features strongly indicated the difference in three various diseases, although all the immunologic markers showed B-cell type. It is concluded that electron microscopic examination is of a definite significance in the diagnosis and successful treatment.     

Hybrid form of hairy cell leukemia and chronic lymphocytic leukemia

We report a case with mixed features of hairy cell leukemia (HCL) and chronic lymphocytic leukemia (CLL), which may represent a hybrid form of these two entities. Hairy projections were demonstrated on leukemic cells in the peripheral blood. Surface marker studies of blood and spleen specimens by flow cytometry and immunohistochemistry showed immunophenotype characteristic of HCL, namely, monoclonal IgG-kappa, positive reactions to CD 11c, CD 19, CD 20, Cd 22, and HLA-DR, but negative reactions to CD 3, CD 5, CD 7 and CD 10. The only atypical finding was the absence of CD 25. Immunogenotyping showed rearrangement of heavy-chain and kappa light chain genes. Leukemic cells were also positive for tartrate-resistant acid phosphatase (TRAP). A pseudosinus pattern was demonstrated in the spleen. However, the leukemic cells in the spleen showed atypical cytologic features. Clinically, the patient had generalized lymphadenopathy, high leukocyte counts, Coombs' negative hemolysis, hypoimmunoglobulinemia and IgG-kappa monoclonal gammopathy, features more consistent with CLL than HCL. Although only CD 11c, CD 22, CD 25 and TRAP are characteristic for HLC and CD 5, characteristic for CLL, a panel of eight markers is recommended for the differential diagnosis of HCL, CLL and other low-grade B-cell neoplasms, which may share some common features, making a clear-cut diagnosis difficult.     

HLA antigens in iranian patients with B-cell chronic lymphocytic leukemia

The frequency of HLA class-I and class-II antigens was investigated in 32 Iranian patients with B-cell chronic lymphocytic leukemia (B-CLL), using the microlymphocytotoxicity method. A significant increase in the HLA-B13 (P<0.01) and DR53 (P < 0.05) and a significant negative association with the A11 (P < 0.05), B35 (P < 0. 05), Cw3 (P < 0.05), and DR1 (P < 0.02) antigens were observed in these patients, compared to the control normal population. These results suggest involvement of some HLA antigens in the multifactorial process of predisposition to B-CLL.