Efficacy and Safety of Bendamustine and Ibrutinib in Previously Untreated Patients With Chronic Lymphocytic Leukemia: Indirect Comparison

Bendamustine and ibrutinib are commonly used in the treatment of patients suffering from chronic lymphocytic leukemia (CLL). In this study we compare efficacy and safety bendamustine versus ibrutinib therapy in previously untreated patients with CLL. Because there are no head-to-head comparisons between bendamustine and ibrutinib, we performed indirect comparison using Bucher method. A systematic literature review was performed and 2 studies published before June 2016 were taken into analysis. Treatment with ibrutinib significantly improves PFS determined by investigator (HR of 0.3; P = .01) and OS (HR of 0.21; P < .001. Our study indicates that ibrutinib therapy improves PFS, OS and is superior in terms of safety comparing with bendamustine therapy in CLL patients.     

**102 Chemoimmunotherapy with Ofatumumab,Fludarabine and Cyclophosphamide (O-FC) in Previously Untreated Patients with Chronic Lymphocytic Leukemia

Results from an international, randomized phase II trial showed that ofatumumab, a human CD20 monoclonal antibody (mAb), in combination with fludarabine and cyclophosphamide (O-FC), was active and well tolerated in treatment-naïve patients with chronic lymphocytic leukemia (CLL), including patients with high-risk disease features.

Full Abstract

Introduction: Chemoimmunotherapy with CD20 mAb is standard frontline treatment for physically fit patients with CLL. Ofatumumab, a human mAb, binds to a membrane-proximal epitope composed of both the small- and large-loop domains of CD20. The pivotal international study of ofatumumab monotherapy demonstrated high overall response rates (ORR) of 47%–58% in patients with fludarabine-refractory CLL. This international, randomized, phase II trial evaluated efficacy and safety of 2 dose levels of

Methods

Previously untreated patients with active CLL were randomized to ofatumumab 500 mg or 1000 mg day 1, with fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 days 2–4, course 1; days 1–3, courses 2–6; every 4 weeks for 6 courses. All patients received ofatumumab 300 mg for course 1. The primary endpoint was complete response (CR) rate, as assessed by an Independent Review Committee using the 1996 NCI-WG criteria.

Results

61 patients were randomized (500 mg, n=31; 1000 mg, n=30). The median (range) age was 56 (38–73) years; 13% of patients had 17p deletion; 64% had β2-microglobulin >3.5 mg/L. CR rate (95% confidence interval [CI]) was 32% (17%–51%) for 500 mg and 50% (31%–69%) for 1000 mg cohort; ORR (95% CI) was 77% (59%–90%) and 73% (54%–88%), respectively. Median progression-free survival (PFS) and overall survival (OS) have not been reached with current follow-up (median 8 months). Based on univariable

Conclusion

O-FC, at the ofatumumab dose levels evaluated, was active in previously untreated patients with CLL, including in patients with high-risk features.

     

Chronic Lymphocytic Leukemia

In recent years, important progress has been made in understanding the pathophysiology, and in improving the diagnosis and treatment, of chronic lymphocytic leukemia (CLL). The characteristics of the B lymphocyte clone are now better defined and disclose great heterogeneity in the mechanisms involved in the development of lymphocytic tumours: both proliferative and apoptotic abnormalities are involved, and a single or recurrent triggering feature is not recognized. Accordingly, the course of the disease is highly variable. Although treatment abstention or deferral for a long period is convenient for many patients, others who present with, or progress to, active CLL will ultimately die from the disease. Clinico-hematological staging systems have greatly clarified the prognostic factors of interest to clinicians, but they remain imprecise in a large category of patients. Recently, other characteristics such as cytogenetics, immunoglobulin gene sequencing, and serum levels of soluble CD23, thymidine kinase and lymphocyte p27 have been recognized as powerful prognostic factors and should now be evaluated in prospective clinical trials. It remains unclear whether any of the available treatments, when indicated, could offer long-term survival benefits for patients. Chlorambucil, purine analogues (including fludarabine or cladribine) and anthracyclinecontaining regimens [i.e. cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)] have been evaluated in large prospective controlled trials, which demonstrated some differences according to response rates, but which failed to disclose any survival advantage, irrespective of the first-line drug treatment allocated. These disappointing results emphasize the need to develop other treatment strategies. Progress could be anticipated in two main ways. Firstly, new, effective and well tolerated treatments with greater specificity are now, or should soon be, available in the clinic: monoclonal antibodies, apoptotic inducers and vaccine systems. Preliminary data suggest that the best use of such treatments is as adjuvant therapy for patients with residual disease, thus complementing the results of chemotherapy. Secondly, intensive treatments with stem-cell rescue (autologous or allogenic) have provided evidence that clonal extinction is an obtainable goal in selected patients, some of whom remain free of any clonal molecular signal for many years. Whether such patients could be considered cured is still unresolved, and this point deserves longer follow-up. Controlled trials are currently exploring this important question. Finally, optimum therapy also aims to improve quality of life, and clinical trials dealing with this important issue, especially in elderly patients, are needed.     

Refractory Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a common malignancy often managed by the practicing oncologist rather than at a tertiary referral center. Since no standard treatment has been shown to be curative, patients are frequently observed without treatment for many years. In the past, first-line therapy with an alkylating agent, particularly chlorambucil, was standard when treatment became necessary. Because of its superior activity in achieving remission and extending the time to relapse and disease progression compared with alkylating agents, the purine nucleoside analog fludarabine is now commonly used as first-line treatment. Historically, salvage treatment with combination chemotherapy included an alkylating agent, anthracycline, vinca alkyloid, and/or corticosteroid. Currently, salvage regimens often incorporate a purine nucleoside analog and an alkylating agent. Two monoclonal antibodies, rituximab and alemtuzumab, have become available and have made further advances in both first-line and salvage treatment of patients with CLL. In this article we review the agents and regimens that have been studied as salvage treatment of CLL. With the development of purine nucleoside analogs and monoclonal antibodies, incremental progress has been made in the therapy of previously treated patients with CLL. Newer strategies will aim to further improve the complete remission rate, which may have a positive impact on survival.     

CD38 ZAP-70在B慢性淋巴细胞白血病中表达及其临床意义的研究

目的:检测CD38及zeta链相关蛋白-70(zeta-associated protein-70,ZAP-70)在B慢性淋巴细胞白血病(B-CLL)中的表达,探讨其与临床的相关性.方法:采用流式细胞仪检测51例B慢性淋巴细胞白血病(B-CLL)患者骨髓或外周血白血病细胞CD38和ZAP-70的表达,结合其与患者临床分期、病情进展、化疗疗效进行分析.结果:1)44例患者中10例(22.73%)CD38和ZAP-70同时表达阳性,22例(50%)CD38和ZAP-70同时表达阴性.2)31例CD38-患者中,初诊时处于Binet B+C期者9例(29.03%);11例CD38+患者中,初诊时处于Binet B+C期者7例(63.64%).CD38阳性、阴性表达在Binet分期上无显著差异(P>0.05).27例ZAP-70-患者中,初诊时处于BinetB+C期者6例(占22.22%);16例ZAP-70+患者中,初诊时处于Binet B+C期者10例(62.5%).ZAP-70阳性、阴性表达在Binet分期上有显著差异(P<0.05).3)23例患者予氟达拉滨单药或联合CTX治疗,16例CD38-表达者中,化疗有效(CR+PR)者11例(68.75%);7例CD38+表达者中,化疗有效者2例(14.29%).11例ZAP-70-表达者中,化疗有效者9例(81.82%);9例ZAP-70+表达者中,化疗有效者1例(11.11%).CD38和ZAP-70阳性、阴性的表达与化疗疗效有显著差异(P<0.05).结论:1)B-CLL患者CD38的表达和ZAP-70的表达有关.2)B-CLL患者ZAP-70阳性、阴性的表达与Binet分期有关系,ZAP-70的阳性表达患者较阴性表达者的病情进展快.3)B-CLL患者CD38和ZAP-70的阳性表达者较阴性表达者的化疗疗效差,预后欠佳.采用流式细胞术检测ZAP-70的表达结合CD38可以作为慢性淋巴白血病的临床分型和预后判断的一个参考指标.     

Richter Syndrome in Chronic Lymphocytic Leukemia

The term Richter syndrome (RS) indicates the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma. RS is a rare complication with an aggressive clinical course, bearing an unfavorable prognosis. In the majority of cases, CLL transforms into RS as diffuse large B cell lymphoma (DLBCL), and a clonal relation between the two processes can be found. However, clonally unrelated RS can occur and transformations to other histologies beside DLBCL have been described. Recent data have shed some light on genetic characteristics that can influence and drive the transformation from CLL to RS. This molecular information has not been translated yet into significant treatment advances, and currently the therapy regimens for RS continue to rely on intensive chemotherapy combinations followed by stem cell transplant in suitable candidates. Based on the rapid pace of discoveries in the field of hematological malignancies and on the recent revolution in the therapeutic landscape for CLL and B cell lymphomas, new therapeutic options for RS might be available in the upcoming years.     

New Agents in Chronic Lymphocytic Leukemia

Despite advances in treatment, chronic lymphocytic leukemia (CLL) remains incurable with standard therapies. Novel therapeutic agents are needed, particularly for patients with high-risk cytogenetic abnormalities such as del(17p13). The past year has seen several advances in this field. The immunomodulatory drug lenalidomide and the cyclin-dependent kinase inhibitor flavopiridol demonstrated clinical activity in fludarabine-refractory CLL patients with high-risk cytogenetic features and bulky lymphadenopathy, but they were associated with toxicities such as tumor flare and tumor lysis. Second-generation monoclonal anti-CD20 antibodies in clinical trials include ofatumumab, which demonstrated activity in fludarabine-refractory patients with bulky lymphadenopathy. Oblimersen, obatoclax, and ABT-263 target the antiapoptotic protein Bcl-2. Investigational agents with novel therapeutic targets include the anti-CD37 small modular immunopharmaceutical TRU-016, the oral spleen tyrosine kinase (Syk) inhibitor fostamatinib, and the oral phosphatidylinositol-3-kinase (PI3K) inhibitor CAL-101; all of these have all shown preliminary evidence of clinical activity. The development of novel agents for treating CLL remains an active, exciting area of research.     

Immune Reconstitution in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is associated with a profound immune defect, which results in increased susceptibility to recurrent infections as well as a failure to mount effective antitumor immune responses. Current chemotherapy-based regimens are not curative and often worsen this immune suppression, so their usefulness is limited, particularly in the frail and elderly. This article reviews the immune defect in CLL and discusses strategies aimed at repairing or circumventing this defect. In particular, it focuses on recent developments in the areas of CD40 ligand (CD40L/CD154) gene therapy, immunomodulatory agents such as lenalidomide, and adoptive transfer of T cells bearing chimeric antigen receptors.     

TNF Receptors in Chronic Lymphocytic Leukemia

Two transmembrane receptors for tumor necrosis factor (TNF) with different molecular weight, 55 kD (p55) and 75 kD (p75), have been identified. In addition, the extracellular part of both receptors are shedded by proteolytic cleavage and exist as soluble receptors which bind to TNF in plasma and other biological fluids. Normal B cells produce TNF and express TNF receptors (R), mainly p75, upon stimulation. TNF costimulates DNA synthesis via the p75 receptor in normal B cells. The B cells from patients with chronic lymphocytic leukemia (CLL) produce TNF and have the capacity to express both receptor types. Also in malignant B cells the p75 receptor is dominant. TNF induce DNA synthesis in CLL cells via both receptors. CLL patients have elevated serum levels of soluble (s) TNFR and this is more pronounced in advanced disease. In conclusion, there is considerable support for TNF as an autocrine growth factor in CLL. However, the net effect of TNF is determined by the quan titative relationship between TNFR on the cell surface, TNF in plasma and sTNFR in plasma, and the affinities between TNF-p55 and TNF-p75. Due to increasing serum levels of sTNFR the significance of TNF as a growth factor is probably less important in advanced disease.     

Ofatumumab,a Novel CD20 Monoclonal Antibody,Is Active in Patients With Fludarabine- and Alemtuzumab-Refractory or Bulky Fludarabine-Refractory Chronic Lymphocytic Leukemia Irrespective of Prior Rituximab

Ofatumumab, a novel CD20 monoclonal antibody, produces high response rates regardless of prior rituximab exposure in patients with fludarabine- and alemtuzumab-refractory or bulky fludarabine-refractory chronic lymphocytic leukemia.Full AbstractBackgroundPatients with CLL refractory to fludarabine and alemtuzumab (FA-ref) or refractory to fludarabine with bulky (> 5 cm) lymphadenopathy (BF-ref) have poor outcomes with current salvage therapy (overall response rate [ORR], 23%; overall survival [OS], 9 months). Ofatumumab is a human monoclonal antibody that binds a distinct membrane-proximal epitope on the CD20 molecule and elicits more efficient in vitro complement-dependent cytotoxicity of B-cell lines and primary tumor cells versus rituximab. We assessed whether prior rituximab exposure impacted outcomes with ofatumumab in patients with FA-ref or BF-ref CLL enrolled in an international, pivotal trial.Patients and MethodsPatients received 8 weekly ofatumumab infusions followed by 4 monthly infusions (infusion, 1300 mg; infusions 2–12, 2000 mg). The primary endpoint was ORR (1996 NCI-WG criteria) assessed by an Independent Endpoint Review Committee over 24 weeks. Secondary efficacy endpoints included progression-free survival (PFS) and OS.ResultsIn the 59 FA-ref and 79 BF-ref patients at the planned interim analysis, ORR was 58% (95% CI, 40%–74%) and 47% (95% CI, 32%-62%), respectively. Median PFS was 5.7 months (95% CI, 4.5–8.0 months) and 5.9 months (95% CI, 4.9–6.4 months), and median OS was 13.7 months (95% CI, 9.4-[not yet reached] months) and 15.4 months (95% CI, 10.2-20.2 months), respectively. In the subgroup of FA-ref (n = 35) and BF-ref (n = 43) patients who previously received a rituximab-containing regimen, ORR was 54% and 44%, and median PFS was 5.5 months (95% CI, 3.7–8.0 months) and 5.5 months (95% CI, 3.8–6.4 months), respectively. In FA-ref and BF-ref patients refractory to fludarabine in combination with rituximab and cyclophosphamide (n = 16 in each group), ORR was 50% and 44%, and median PFS was 4.6 months (95% CI, 2.3–6.4 months) and 5.6 months (95% CI, 2.1–6.6 months), respectively.ConclusionSingle-agent ofatumumab is active in patients with FA-ref and BF-ref CLL, irrespective of prior anti-CD20 monoclonal antibody therapy with rituximab, including refractoriness to fludarabine-based regimens containing rituximab.     

Chylous Effusion Complicating Chronic Lymphocytic Leukemia

We present a case of chylous effusion (CE) occurring in a patient with chronic lymphocytic leukemia (CLL), an observation which has rarely been reported. Therefore, CLL should be added to the differential diagnosis of nontraumatic chylothorax. CE in CLL can be successfully managed by irradiation of the mediastinum.     

Prognostic Factors for Chronic Lymphocytic Leukemia

As novel strategies for treatment and prognostication of chronic lymphocytic leukemia (CLL) evolve, the traditional Rai and Binet systems can now be updated with more modern prognostic markers. This is a review of the latest articles which combine studies from major CLL centers to summarize major prognostic factors for patients diagnosed with CLL. The prognostic information can be categorized into three categories: genetic abnormalities which include 17p, 11q, and immunoglobulin heavy chain variable (IGHV) abnormalities; biochemical abnormalities and cell surface markers which include serum thymidine kinase, β-2-microglobulin, CD49d, CD38, and ZAP-70 levels; and patient characteristics which include sex, age, and performance status.