HMDS
Contributions
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:30 to 14.06.2015 08:45
Location: Room A7
Background
Ibrutinib is a Bruton’s tyrosine kinase inhibitor with efficacy in CLL. The IcICLLe trial (ISRCTN 12695354) is a feasibility study to investigate the biological response to ibrutinib and inform the design of subsequent randomised phase II/III trial(s). Primary outcome measures include assessment of the CLL cell levels and protein expression profile, particularly in relation to cell cycle and other CLL treatment targets, in the peripheral blood (PB) and bone marrow (BM). Toxicity, categorical response and survival are secondary outcomes.
Aims
To understand the biological impact of ibrutinib treatment and identify changes that may impact the design of therapeutic strategies or affect disease monitoring.
Methods
40 participants with CLL requiring treatment (20 treatment-naïve and 20 relapsed/refractory) received ibrutinib (420 mg once daily) from registration until either achievement of <0.01% residual disease in bone marrow or disease progression. PB & BM samples are taken -0.5 (screening), 1 & 6 months with additional PB samples at 0 (baseline), 4 hours, 1, 2, 7, & 14 days and 2, 9, & 12 months (M). Markers assessed at each time point include CD19, CD20, CD45, CD5, CD10, CD305, kappa, lambda, CD23, CD43, CD81, CD79b, ROR1, CXCR4, CD49d, Ki67, CD62L, and CD38 with an additional 30 markers (including BCL2, ZAP-70 and IRF4) samples with paired PB & BM.
Results
Absolute peripheral B-cell counts increased immediately after the first dose, peaking at two weeks, and returning to baseline by month 2 (median 1.25, 1.44, 2.1, 1.19 fold absolute B-cell count relative to baseline at 4hrs, 24hrs, 2 weeks and 2 months after first dose respectively). There was no difference in bone marrow infiltration after 1 month of treatment but after 6 months, 7/8 evaluable patients had more than 50% reduction in PB CLL counts relative to baseline and bone marrow involvement was reduced with 3/8 achieving <30% BM CLL and 1 treatment-naïve patient achieving a CR.
The proportion of CLL cells expressing Ki67 at baseline was slightly lower in the peripheral blood (median 3.5%, range 0.3-22.3%) than the bone marrow (median 3.9%, range 0.8-42%) but the difference was not significant and blood was a suitable site for assessing proliferative capacity. Ki67 expression initially increased, peaking at 24 hours after first dose (PB CLL Ki67+ median 5.1%, range 0.4-16.4%), after which the Ki67 expression declined below quantifiable levels (<0.5%) in 15% of patients by week 1 and in more than 90% of patients at subsequent time points. Similarly in the BM, CLL Ki67 expression was not detectable in most patients after 1 month of treatment. Other changes in protein expression during treatment, including decreases in markers associated with proliferation in CLL (CD5, CD23, CD38, CD49d and IRF4), and changes in molecules involved in CLL cell trafficking and adhesion (increased CXCR4 and CD24 expression; decreased CCR7, CD31 and CD11a) followed the same kinetics as cell cycle arrest, i.e. differences emerged after 1-2 weeks of treatment and then stabilised during subsequent treatment. Concerning molecules involved in disease monitoring, CD19, CD5 & CD43 expression were mildly reduced but overall expression remained strong; CD81/CD79b expression did not change significantly; CD20/CD22 expression decreased, potentially enhancing discrimination from normal B-cells but this may affect optimal timing of anti-CD20 therapy; CD200 expression was also consistently decreased and these changes need to be considered when assessing residual disease levels.
Summary
The redistribution of CLL cells during ibrutinib therapy happens much more rapidly than any changes in proteins associated with proliferation, cell trafficking or adhesion. The majority of changes in CLL cells correlate with the loss of the proliferative fraction, mostly stabilising after one month of treatment.
Keyword(s): Chronic lymphocytic leukemia, Kinase inhibitor, Outcome, Proliferation
Session topic: CLL: Refining outcomes
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:30 to 14.06.2015 08:45
Location: Room A7
Background
Ibrutinib is a Bruton’s tyrosine kinase inhibitor with efficacy in CLL. The IcICLLe trial (ISRCTN 12695354) is a feasibility study to investigate the biological response to ibrutinib and inform the design of subsequent randomised phase II/III trial(s). Primary outcome measures include assessment of the CLL cell levels and protein expression profile, particularly in relation to cell cycle and other CLL treatment targets, in the peripheral blood (PB) and bone marrow (BM). Toxicity, categorical response and survival are secondary outcomes.
Aims
To understand the biological impact of ibrutinib treatment and identify changes that may impact the design of therapeutic strategies or affect disease monitoring.
Methods
40 participants with CLL requiring treatment (20 treatment-naïve and 20 relapsed/refractory) received ibrutinib (420 mg once daily) from registration until either achievement of <0.01% residual disease in bone marrow or disease progression. PB & BM samples are taken -0.5 (screening), 1 & 6 months with additional PB samples at 0 (baseline), 4 hours, 1, 2, 7, & 14 days and 2, 9, & 12 months (M). Markers assessed at each time point include CD19, CD20, CD45, CD5, CD10, CD305, kappa, lambda, CD23, CD43, CD81, CD79b, ROR1, CXCR4, CD49d, Ki67, CD62L, and CD38 with an additional 30 markers (including BCL2, ZAP-70 and IRF4) samples with paired PB & BM.
Results
Absolute peripheral B-cell counts increased immediately after the first dose, peaking at two weeks, and returning to baseline by month 2 (median 1.25, 1.44, 2.1, 1.19 fold absolute B-cell count relative to baseline at 4hrs, 24hrs, 2 weeks and 2 months after first dose respectively). There was no difference in bone marrow infiltration after 1 month of treatment but after 6 months, 7/8 evaluable patients had more than 50% reduction in PB CLL counts relative to baseline and bone marrow involvement was reduced with 3/8 achieving <30% BM CLL and 1 treatment-naïve patient achieving a CR.
The proportion of CLL cells expressing Ki67 at baseline was slightly lower in the peripheral blood (median 3.5%, range 0.3-22.3%) than the bone marrow (median 3.9%, range 0.8-42%) but the difference was not significant and blood was a suitable site for assessing proliferative capacity. Ki67 expression initially increased, peaking at 24 hours after first dose (PB CLL Ki67+ median 5.1%, range 0.4-16.4%), after which the Ki67 expression declined below quantifiable levels (<0.5%) in 15% of patients by week 1 and in more than 90% of patients at subsequent time points. Similarly in the BM, CLL Ki67 expression was not detectable in most patients after 1 month of treatment. Other changes in protein expression during treatment, including decreases in markers associated with proliferation in CLL (CD5, CD23, CD38, CD49d and IRF4), and changes in molecules involved in CLL cell trafficking and adhesion (increased CXCR4 and CD24 expression; decreased CCR7, CD31 and CD11a) followed the same kinetics as cell cycle arrest, i.e. differences emerged after 1-2 weeks of treatment and then stabilised during subsequent treatment. Concerning molecules involved in disease monitoring, CD19, CD5 & CD43 expression were mildly reduced but overall expression remained strong; CD81/CD79b expression did not change significantly; CD20/CD22 expression decreased, potentially enhancing discrimination from normal B-cells but this may affect optimal timing of anti-CD20 therapy; CD200 expression was also consistently decreased and these changes need to be considered when assessing residual disease levels.
Summary
The redistribution of CLL cells during ibrutinib therapy happens much more rapidly than any changes in proteins associated with proliferation, cell trafficking or adhesion. The majority of changes in CLL cells correlate with the loss of the proliferative fraction, mostly stabilising after one month of treatment.
Keyword(s): Chronic lymphocytic leukemia, Kinase inhibitor, Outcome, Proliferation
Session topic: CLL: Refining outcomes