Persistent janus kinase-signaling in chronic lymphocytic leukemia patients on ibrutinib: Results of a phase I trial

Abstract

Methods to deepen clinical responses to ibrutinib are needed to improve outcomes for patients with chronic lymphocytic leukemia (CLL). This study aimed to determine the safety and efficacy of combining a janus kinase (JAK)-inhibitor with ibrutinib because JAK-mediated cytokine-signals support CLL cells and may not be inhibited by ibrutinib. The JAK1/2 inhibitor ruxolitinib was prescribed to 12 CLL patients with abnormal serum beta-2 microglobulin levels after 6 months or persistent lymphadenopathy or splenomegaly after 12 months on ibrutinib using a 3 + 3 phase 1 trial design (NCT02912754). Ibrutinib was continued at 420 mg daily and ruxolitinib was added at 5, 10, 15, or 20 mg BID for 3 weeks out of five for seven cycles. The break was mandated to avoid anemia and thrombocytopenia observed with ruxolitinib as a single agent in CLL. The combination was well-tolerated without dose-limiting toxicities. Cyclic changes in platelets, lymphocytes, and associated chemokines and thrombopoietic factors were observed and partial response criteria were met in 2 of 12 patients. The results suggest that JAK-signaling helps CLL cells persist in the presence of ibrutinib and ruxolitinib with ibrutinib is well-tolerated and may be a useful regiment to use in combination therapies for CLL.

Keywords: chemokines; chronic lymphocytic leukemia; ibrutinib; janus kinases; ruxolitinib; thrombopoiesis.

Conflict of interest statement

D. E. Spaner reports grants from Novartis to support the submitted work and personal fees from Janssen outside the submitted work. The other authors declare no conflicts of interest with respect to this work.

© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

Figure 1

Effect of ruxolitinib on hemoglobin (Hb), platelets, and β2M. (A) Hb was measured before starting ruxolitinib while on ibrutinib (C1D1) and after completing the seventh cycle of ruxolitinib (C7D21). The lines indicate results for individual patients and data for groups 1 and 2 (5 and 10 mg ruxolitinib) and groups 3 and 4 (15 and 20 mg ruxolitinib) are shown in different graphs. (B) Platelet counts were measured at C1D1 and at end of treatment (EOT). (C) β2M was measured at each time‐point and normalized to the initial value at C1D1. The average and standard error of these ratios for all patients are plotted as a function of time and show that β2M levels decreased during treatment with ruxolitinib (indicated by the solid bars labeled “C”) but recovered during the 2 week break from ruxolitinib in each cycle (indicated by the dashed bars labeled “B”). *P < 0.05; ns, not significant

Figure 2

Effect of ruxolitinib on blood lymphocytes. (A) Lymphocyte numbers at each time‐point were taken from the medical record. Differences between lymphocyte counts at each time‐point and the initial count at C1D1 were plotted as a function of time. Each line represents results for an individual patient. Groups 1 and 2 are distinguished from groups 3 and 4. The bars labeled C1, C2, C3, etc. represent the 3‐week period on ruxolitinib during each treatment cycle. Results for JAK2011 were considered uninterpretable as a result of confounding clinical events not related to the trial and were not included in the analysis. (B) Blood from JAK2014 was collected at C6D21, C7D1, and C7D21 and analyzed by 10‐color flow cytometry. Percentages of selected lymphocyte populations at each time‐point are shown below the respective dot‐plots and suggest CD5+ CD19+ CLL cells and CD38+ NK cells cycle in and out of the blood in the presence and absence of ruxolitinib

Figure 3

Effect of ruxolitinib on platelets and thrombopoietic cytokines. (A) Platelet counts were taken from the medical record. Differences between the number at each time‐point and initial platelet count at C1D1 were plotted as a function of time. Each line represents the calculations for a single patient. Results for groups 1 and 2 are shown separately from groups 3 and 4. (B‐D) TPO (B), PDGF‐AA (C, right panel), and CD40L (D, right panel) were measured in plasma from bone marrow aspirates obtained at C1D1 and CD3D21. PDGF‐AA (C, left panel) and CD40L (D, left panel) were also measured in plasma from blood at day 1 and day 21 of a treatment cycle. Each line represents results for an individual patient. *P < 0.05

Figure 4

Effect of ruxolitinib on IL10, CXCL10, and CXCL1. IL10, CXCL10, and CXCL1 were measured in plasma from blood at day 1 and day 21 of a treatment cycle (left panels) and also in plasma from marrow aspirates obtained at C1D1 and CD3D21 (right panels). Each line represents results for an individual patient. *P < 0.05