Low-dose thalidomide in combination with oral fludarabine and cyclophosphamide is ineffective in heavily pre-treated patients with chronic lymphocytic leukemia

Laurenti, Luca; Piccioni, Paola; Tarnani, Michela; Padua, Laura De; Garzia, Mariagrazia; Efremov, Dimitar G.; Piccirillo, Nicola; Chiusolo, Patrizia; Sica, Simona; Leone, Giuseppe

doi:10.1016/j.leukres.2006.05.013

Cited by 17 publications

(8 citation statements)

References 8 publications

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“…study was similar to ours with fatigue, constipation and peripheral neuropathy [12]. A more recent trial combined thalidomide along with oral fludarabine and cyclophosphamide [13] for previously treated CLL but reported it to not be as effective as the former trial of thalidomide and fludarabine [12]. This is likely due to the heavily pretreated cohort of CLL in this latter trial.…”

Section: Discussionsupporting

confidence: 70%

N9986: a phase II trial of thalidomide in patients with relapsed chronic lymphocytic leukemia

Kay

Shanafelt

Call

et al. 2009

Leukemia & Lymphoma

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We enrolled 28 eligible patients with relapsed chronic lymphocytic leukemia (CLL) to a phase II study of single agent thalidomide (200 mg/d, with dose escalation up to 1000 mg/d over 60 days). The median age was 66 years and 71% were males. Study participants received a median of 2 (range 1–7) prior treatment regimens and 61% had Rai stage 3–4 disease at enrollment. Grade 3 or higher hematologic toxicity was observed in 13 (46%) and 16 (57%) had grade 3 or higher non-hematologic toxicity. Grade 3–4 tumor flare was observed in five (18%) patients. The overall response rate was 11% (3 of 28) with one (4%) complete remission and two (7%) partial remissions. Duration of response for these three responders was 3, 14 and 15 months. Fourteen (50%) patients had stabilisation of disease for a median duration of 8 months (95% CI: 7–16 months). Median time to progression for all 28 patients was 7.3 months. Although thalidomide appears to have modest clinical activity in pretreated/relapsed CLL primarily based on reduction of the absolute lymphocyte count, in our opinion the toxicity profile precludes it from more active investigation in CLL.

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Section: Discussionsupporting

confidence: 70%

N9986: a phase II trial of thalidomide in patients with relapsed chronic lymphocytic leukemia

Kay

Shanafelt

Call

et al. 2009

Leukemia & Lymphoma

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“…24 In heavily pretreated patients with CLL, failure of treatment with thalidomide, fludarabine and cyclophosphamide was associated with an increase of TNF serum level. 25 In the current study, we observed a tendency toward an increase of TNF serum levels in thalidomide nonresponders. Moreover, these cases presented with higher levels of TNF-R1, TNF-R2 as well as TNF expression at diagnosis.…”

Section: Discussionsupporting

confidence: 57%

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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“…THAL might not only target the CLL cell population but also decrease the number of T regs , and thereby restore the CD8 þ T-cell function in treated patients. Laurenti et al 6 compared the efficacy and toxicity of a therapy combining THAL with oral FLU and cyclophosphamide in heavily pretreated patients with progressive CLL, and monitored the effects of this treatment on the serum TNF level. None of the patients responded to the therapy.…”

Section: Cd25mentioning

confidence: 99%

“…None of the patients responded to the therapy. Laurenti et al 6 concluded that ineffective treatment correlated with increasing levels of TNF observed during the therapy. In contrast, we observed increasing levels of TNF as well as of interleukin (IL Elevated levels of TNF were associated with progressive disease in patients with B-CLL and increased with the stage of the disease.…”

Section: Cd25mentioning

confidence: 99%

The high frequency of T regulatory cells in patients with B-cell chronic lymphocytic leukemia is diminished through treatment with thalidomide

et al. 2007

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Low-dose thalidomide in combination with oral fludarabine and cyclophosphamide is ineffective in heavily pre-treated patients with chronic lymphocytic leukemia

Cited by 17 publications

References 8 publications

N9986: a phase II trial of thalidomide in patients with relapsed chronic lymphocytic leukemia

N9986: a phase II trial of thalidomide in patients with relapsed chronic lymphocytic leukemia

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

The high frequency of T regulatory cells in patients with B-cell chronic lymphocytic leukemia is diminished through treatment with thalidomide

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