Phase I study of lenalidomide and alemtuzumab in refractory chronic lymphocytic leukaemia: maintaining immune functions during therapy‐induced immunosuppression
“…3c). The decrease in T regs observed in part I of the study [25] was confirmed in the present extended analysis ( p = 0.003) (Fig. 3d).Fig.…”
Section: Resultssupporting
confidence: 87%
“…2a, b), and then, normalization gradually occurred. As preliminarily reported earlier [25], a significant increase was observed in the frequency of activated (HLA-DR + ) T cells after single-agent lenalidomide treatment. The frequency increased further during the combination therapy, and HLA-DR + cells increased from 25% at baseline to 82% at week 16 within the CD4 + subset ( p = 0.0009) and from 33 to 89% in the CD8 + subset ( p = 0.0017) (Fig.…”
Section: Resultssupporting
confidence: 78%
“…Four of these patients progressed early, and the dose was considered ineffective in advanced-phase progressive CLL [25]. After an amendment, the subsequent 17 patients received a starting dose of 5 mg/day.…”
Section: Resultsmentioning
confidence: 99%
“…Lenalidomide was given continuously as a single agent for weeks 1–4 at a starting dose of 2.5 mg/day in patients 1–6 and 5 mg/day in patients 7–23 [25]. Alemtuzumab was added at week 5 (30 mg s.c. three times a week), and lenalidomide was then escalated stepwise (5–10–15 mg/day) depending on tolerability.…”
Section: Methodsmentioning
confidence: 99%
“…Results of a phase I study, in which 12 refractory CLL patients were included, have previously been reported [25]. In the present report, the complete analysis of totally 23 patients is described, with a focus on analysis of changes in T cell subsets, including immune checkpoints as well as cell activation, proliferation and cytotoxic markers.…”
This phase I–II study explored safety, immunomodulatory and clinical effects of lenalidomide (weeks 1–16) and alemtuzumab (weeks 5–16) in 23 patients with refractory chronic lymphocytic leukemia. Most patients had Rai stage III/IV disease and were heavily pretreated (median 4 prior therapies), and 61% had del(17p)/del(11q). Eleven of 19 evaluable patients (58%) responded, with a median response duration of 12 months (1–29+); time to progression was short in non-responders. Lenalidomide had a narrow therapeutic dose range, 2.5 mg/day was not efficient, and maximum tolerated dose was 5 mg/day. Grade 3–4 neutropenia and thrombocytopenia occurred in 84 and 55%, 30% had febrile neutropenia, and CMV-reactivation requiring valganciclovir occurred in 30% of patients. The frequency of proliferating (Ki67+) CD8+ T cells was increased at week 4, with further increase in both the CD4+ and CD8+ subsets (p < 0.01 and <0.05), which was accompanied by significant upregulation of HLA-DR after addition of alemtuzumab. Antigen-experienced cells increased at week 4 as the frequency of effector memory cells increased in the CD8+ subset (p < 0.003), while effector cells decreased in both the CD8+ and CD4+ subsets (p < 0.0001 and p < 0.01). The Th1/Th2 balance was unchanged at week 4 but shifted toward a Th2 profile after combination therapy. At end of treatment, the frequency of Th17 and regulatory T cells was reduced (p < 0.01), naïve T cells decreased, and effector memory T cells increased (p < 0.05 and p < 0.01). Granzyme B+ T cells increased at 30-week follow-up (p < 0.05). PD-1 expression was unaffected. In conclusion, low-dose lenalidomide and alemtuzumab induced major perturbations of T cells, including increased proliferative activity and cytotoxic potential.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-016-1922-6) contains supplementary material, which is available to authorized users.
“…3c). The decrease in T regs observed in part I of the study [25] was confirmed in the present extended analysis ( p = 0.003) (Fig. 3d).Fig.…”
Section: Resultssupporting
confidence: 87%
“…2a, b), and then, normalization gradually occurred. As preliminarily reported earlier [25], a significant increase was observed in the frequency of activated (HLA-DR + ) T cells after single-agent lenalidomide treatment. The frequency increased further during the combination therapy, and HLA-DR + cells increased from 25% at baseline to 82% at week 16 within the CD4 + subset ( p = 0.0009) and from 33 to 89% in the CD8 + subset ( p = 0.0017) (Fig.…”
Section: Resultssupporting
confidence: 78%
“…Four of these patients progressed early, and the dose was considered ineffective in advanced-phase progressive CLL [25]. After an amendment, the subsequent 17 patients received a starting dose of 5 mg/day.…”
Section: Resultsmentioning
confidence: 99%
“…Lenalidomide was given continuously as a single agent for weeks 1–4 at a starting dose of 2.5 mg/day in patients 1–6 and 5 mg/day in patients 7–23 [25]. Alemtuzumab was added at week 5 (30 mg s.c. three times a week), and lenalidomide was then escalated stepwise (5–10–15 mg/day) depending on tolerability.…”
Section: Methodsmentioning
confidence: 99%
“…Results of a phase I study, in which 12 refractory CLL patients were included, have previously been reported [25]. In the present report, the complete analysis of totally 23 patients is described, with a focus on analysis of changes in T cell subsets, including immune checkpoints as well as cell activation, proliferation and cytotoxic markers.…”
This phase I–II study explored safety, immunomodulatory and clinical effects of lenalidomide (weeks 1–16) and alemtuzumab (weeks 5–16) in 23 patients with refractory chronic lymphocytic leukemia. Most patients had Rai stage III/IV disease and were heavily pretreated (median 4 prior therapies), and 61% had del(17p)/del(11q). Eleven of 19 evaluable patients (58%) responded, with a median response duration of 12 months (1–29+); time to progression was short in non-responders. Lenalidomide had a narrow therapeutic dose range, 2.5 mg/day was not efficient, and maximum tolerated dose was 5 mg/day. Grade 3–4 neutropenia and thrombocytopenia occurred in 84 and 55%, 30% had febrile neutropenia, and CMV-reactivation requiring valganciclovir occurred in 30% of patients. The frequency of proliferating (Ki67+) CD8+ T cells was increased at week 4, with further increase in both the CD4+ and CD8+ subsets (p < 0.01 and <0.05), which was accompanied by significant upregulation of HLA-DR after addition of alemtuzumab. Antigen-experienced cells increased at week 4 as the frequency of effector memory cells increased in the CD8+ subset (p < 0.003), while effector cells decreased in both the CD8+ and CD4+ subsets (p < 0.0001 and p < 0.01). The Th1/Th2 balance was unchanged at week 4 but shifted toward a Th2 profile after combination therapy. At end of treatment, the frequency of Th17 and regulatory T cells was reduced (p < 0.01), naïve T cells decreased, and effector memory T cells increased (p < 0.05 and p < 0.01). Granzyme B+ T cells increased at 30-week follow-up (p < 0.05). PD-1 expression was unaffected. In conclusion, low-dose lenalidomide and alemtuzumab induced major perturbations of T cells, including increased proliferative activity and cytotoxic potential.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-016-1922-6) contains supplementary material, which is available to authorized users.
Interleukin (IL)-10-producing B cells (B10 cells) have emerged as important regulatory players with immunosuppressive roles. Chronic lymphocytic leukemia (CLL) B cells also secrete IL-10 and share features of B10 cells, suggesting a possible contribution of CLL B cells to immunosuppression in CLL patients. Factors controlling the emergence of B10 cells are not known. B cell-activating factor of the tumour necrosis factor (TNF) family (BAFF) is critical for B cell maturation and survival, and is implicated in the development and progression of CLL. We sought to investigate the role of BAFF in the emergence of IL-10-producing B regulatory cells in healthy donors and CLL patients. Here, we report that BAFF signaling promotes IL-10 production by CLL B cells in a mouse model of CLL and in CLL patients. Moreover, BAFF-mediated IL-10 production by normal and CLL B cells is mediated via its receptor TACI. Our work uncovered a major targetable pathway important for the generation of regulatory B cells that is detrimental to immunity in CLL.
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