Activity of the Janus kinase inhibitor ruxolitinib in chronic lymphocytic leukemia: results of a phase II trial

David E Spaner, Guizhei Wang, Lindsay McCaw, Yanmei Li, Patricia Disperati, Mary-Ann Cussen, Yonghong Shi, David E Spaner, Guizhei Wang, Lindsay McCaw, Yanmei Li, Patricia Disperati, Mary-Ann Cussen, Yonghong Shi

No abstract available

Keywords: Ibrutinib; Janus Kinases; Kinase inhibitors; Ruxolitinib; STAT3; chronic lymphocytic leukemia; phosphoproteome.

Figures

Figure 1.

Ruxolitinib-induced changes in adenopathy, lymphocytosis, LDH, β2M, phospho-STAT3/5, miR-17, and cytokines. (A) A lymphadenopathy score defined as the sum of the products of bidimensional measurements of the largest palpable lymph nodes plus the length of the spleen in cm below the costal margin was recorded at each clinic visit. WBCs, β2M and LDH at each visit, at the end of treatment (EOT), and 30 days after stopping Ruxolitinib were also recorded. The average and standard error of the percent differences in each of these measurements from the baseline values at cycle 1 are shown for each time-point. (B) Clinical course of JAK14 where Ruxolitinib was held due to low platelet counts and restarted several weeks later. Circulating lymphocytes and LDH levels increased rapidly each time Ruxolitinib was started but returned to baseline levels or lower when Ruxolitinib was held. LDH and WBC counts are normalized to the values at cycle 1. Initial lymphocyte counts, β2M, and LDH values for each patient are shown in Table 1. (C) Upper panel: Phospho-proteins in CLL cells obtained pre-treatment at cycle 1 and post-treatment at cycle 3 were measured with kits (#ARY003B) from R&D (Minneapolis, MN, USA). These times were chosen since lymphadenopathy scores and β2M levels had clearly decreased by cycle 3 (Figure 1A). STAT5A/B phosphorylated at tyrosine residues 694 and Y699 and STAT3 phosphorylated at Y705 were quantified by densitometry and the sums of these values are indicated in the graph. Lower panel: miR-17 expression was measured at these times by quantitative real-time PCR as before. (D) Plasma collected before each treatment cycle was analyzed by multiplex laser-bead technology (Eve Technologies, Calgary, AB). The summary graph indicates GCSF levels before treatment and the greatest change following treatment with Ruxolitinib. *P<0.05.