Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL)

Chanan‐Khan, Asher; Miller, Kena C.; Takeshita, Kenichi; Koryzna, Alexandra; Donohue, Kathleen; Bernstein, Zale P.; Mohr, Alice; Klippenstein, Donald; Wallace, Paul K.; Zeldis, Jerome B.; Berger, C.; Czuczman, Myron S.

doi:10.1182/blood-2005-02-0669

Cited by 90 publications

(39 citation statements)

References 23 publications

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“…Although thalidomide has proved to be effective for patients with MM, 21 recently first promising results were also reported in treatment-naive patients with CLL with five complete and four partial remissions in nine patients completing six courses of thalidomide/fludarabine therapy. 11 Furthermore, in this study thalidomide was reported to reduce the WBC after 1 week of treatment. 11 In the current study, we investigated a larger cohort composed mostly of IgVH unmutated cases with CLL.…”

Section: Discussionmentioning

confidence: 99%

“…11 Furthermore, in this study thalidomide was reported to reduce the WBC after 1 week of treatment. 11 In the current study, we investigated a larger cohort composed mostly of IgVH unmutated cases with CLL. We could demonstrate that thalidomide/fludarabine represents a feasible therapeutic option for patients with CLL with encouraging data especially for treatment-naive cases.…”

Section: Discussionmentioning

confidence: 99%

“…10 Thus, thalidomide-based treatment might represent a novel therapeutic strategy for patients with CLL, and it has been suggested that the addition of fludarabine might enhance its antileukemic effect. 11 Furthermore, in CLL higher proportions of CD4 þ CD25 hi FOXP3 þ regulatory T cells (Tregs) have been described. 12 Although Tregs are potent to inhibit immune response in CLL including T-cell responses against tumor antigens, their increased percentages were normalized after effective treatment with fludarabine.…”

Section: Introductionmentioning

confidence: 99%

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Thalidomide exerts distinct molecular antileukemic effects and combined thalidomide/fludarabine therapy is clinically effective in high-risk chronic lymphocytic leukemia

et al. 2009

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Thalidomide represents a promising immunomodulatory drug that targets both leukemia cells and the tumor microenvironment. We treated patients with chronic lymphocytic leukemia (CLL) with a combined thalidomide/fludarabine regimen and monitored cellular and molecular changes induced by thalidomide in vivo before fludarabine treatment. Thalidomide was given daily (100 mg p.o. per day) and fludarabine was administered on days 7-11 (25 mg/m 2 i.v. per day) within each 4-week cycle (maximum of 6 cycles). Twenty patients received thalidomide/fludarabine as first-line therapy and 20 patients were previously treated. Unmutated IgVH mutation status was found in 36 cases and 13 had high-risk cytogenetic aberrations (del17p, del11q). The overall response rate was 80 and 25% for untreated and previously treated patients, respectively. Although thalidomide reduced the number of CLL cells, the number of CD3 lymphocytes showed no significant change, but the number of CD4 þ CD25 hi FOXP3 þ regulatory T cells (Tregs) was significantly decreased. Gene expression profiling revealed a thalidomide-induced signature containing both targets known to have a function in immunomodulatory drug action as well as novel candidate genes. Combined thalidomide/fludarabine therapy demonstrated efficacy in high-risk patients with CLL. Furthermore, our study provides novel biological insights into thalidomide effect, which might act by enhancing apoptosis of CLL cells and reducing Tregs, thereby enabling T-cell-dependent antitumor effect.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Thalidomide exerts distinct molecular antileukemic effects and combined thalidomide/fludarabine therapy is clinically effective in high-risk chronic lymphocytic leukemia

et al. 2009

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“…72 Thalidomide has shown single-agent activity in CLL: it induced a median 55% decrease in lymphocytosis in treated patients. 73 In a recently reported experience, thalidomide was used in combination with fludarabine in 20 previously untreated patients. The overall response rate was 100% and complete responses or nodular partial responses were achieved in 65% of the patients.…”

Section: Antiangiogenic Therapy In Cllmentioning

confidence: 99%

Role of angiogenesis in chronic lymphocytic leukemia

Letilović

Vrhovać

Verstovšek

et al. 2006

Cancer

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Angiogenesis is a physiologic process of new blood vessels formation mediated by various cytokines called angiogenic and angiostatic factors. Although its potential pathophysiologic role in solid tumors has been extensively studied for more than 3 decades, enhancement of angiogenesis in chronic lymphocytic leukemia (CLL) and other malignant hematological disorders has been recognized more recently.An increased level of angiogenesis has been documented by various experimental methods both in bone marrow and lymph nodes of patients with CLL. Although the role of angiogenesis in the pathophysiology of this disease remains to be fully elucidated, experimental data suggest that several angiogenic factors play a role in the disease progression. Biologic markers of angiogenesis were also shown to be of prognostic relevance in CLL. The current findings provide the rationale for investigating antiangiogenic agents in CLL. In the current review angiogenesis in CLL is discussed and its potential diagnostic and therapeutic applications. Cancer 2006;107:925-34.

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“…Immunomodulatory agents have made an impact in various hematologic malignancies, especially those of B-cell origin. In a phase I/II study of thalidomide and fludarabine in previously untreated CLL, Chanan-Khan et al, reported an ORR of 100% [6]. This obse-rvation led to the investigation of lenalidomide in CLL, which as a single agent in doi: 10.7243/2052-434X-3-2 the relapsed/refractory setting, demonstrated an ORR of 58% with a CR rate of 18% [7,8].…”

Section: Introductionmentioning

confidence: 99%

Lenalidomide following fludarabine and rituximab in previously untreated CLL

Ujjani¹,

Paulus²,

Gehan³

et al. 2015

Hematol Leuk

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Fludarabine-based regimens have overall response rates (ORR) of 90-95% in untreated chronic lymphocytic leukemia (CLL), but almost all patients inevitably relapse. Given the promising activity of lenalidomide in relapsed/refractory CLL, we studied the combination of fludarabine and rituximab (FR) followed by lenalidomide in untreated disease (n=22). Patients received three cycles (C) of FR (F 25 mg/m 2 days (D) 1-5, R 375 mg/m 2 D1). Those who responded received three more cycles of FR followed by three cycles of lenalidomide; whereas patients with stable or progressive disease switched to lenalidomide (5 mg C1D1-21, 10 mg in subsequent cycles). After three cycles of lenalidomide, patients with a response or stable disease received another three cycles, whereas those who progressed were removed. The ORR with FR was 77% (complete response (CR) 23%). With lenalidomide (n=15), three converted from a partial response to CR, increasing the CR rate to 36%. The most common >grade 3 toxicity was neutropenia (59%). The median progression-free survival was 38.5 months (95% CI: 32.0, 53.9) and the median overall survival had not yet been reached at the time of analysis. The study demonstrated the feasibility of FR-L when administered in a sequential manner.

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Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL)

Cited by 90 publications

References 23 publications

Thalidomide exerts distinct molecular antileukemic effects and combined thalidomide/fludarabine therapy is clinically effective in high-risk chronic lymphocytic leukemia

Thalidomide exerts distinct molecular antileukemic effects and combined thalidomide/fludarabine therapy is clinically effective in high-risk chronic lymphocytic leukemia

Role of angiogenesis in chronic lymphocytic leukemia

Lenalidomide following fludarabine and rituximab in previously untreated CLL

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