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Global Hematology 2019

Hematology and Blood Disorders | Volume 2

Page 13

July 25-26, 2019 | Amsterdam, Netherlands

OF EXCELLENCE

IN INTERNATIONAL

MEETINGS

alliedacademies.com

YEARS

4

th

International Conference on

HEMATOLOGY AND

BONE MARROW TRANSPLANTATION

SCIENTIFIC RATIONALE FOR LOWER

DOSE OF IBRUTINIB IN PATIENTS WITH

CHRONIC LYMPHOCYTIC LEUKEMIA

I

brutinib (Imbruvica®) is a revolutionary and FDA approved agent for chronic

lymphocytic leukemia (CLL). This oral drug covalently and irreversibly binds to

the C481 residue of Bruton’s tyrosine kinase (BTK); a pivotal enzyme in the B-cell

receptor pathway. The standard ibrutinib dose for CLL is 420 mg/d, which was se-

lected from a Phase I study of ibrutinib in patients with relapsed/refractory B-cell

malignancies. Although ibrutinib is well tolerated, intolerance and adverse events

(AEs) are major causes of discontinuation of ibrutinib. In addition to the issues of

safety and tolerability, the cost of ibrutinib in the United States exceeds $130,000/

year for patients with CLL. Furthermore, since complete remissions with ibrutinib

are rare, either indefinite administration of the drug or combination strategies

are required. Previously they demonstrated a decline in BTK protein levels in CLL

cells after cycle 1 of ibrutinib, suggesting that the ibrutinib dose could be lowered

after the first cycle without loss of biological effect. To test this postulate, a pilot

study was designed to systematically reduce ibrutinib dosing within the same pa-

tient with CLL over three 28-day cycles. Following an initial cycle of 420 mg/d, the

dose was reduced to 280 mg/d in cycle 2 and then to 140 mg/d in cycle 3. Eleven

patients began study treatment, and nine completed the 3 cycles. Plasma and

intracellular levels of ibrutinib were dose-dependent and even the lowest dose

was sufficient to occupy on average >95% of BTK protein. In concert, BTK down-

stream signalling inhibition was maintained with 140 mg/d ibrutinib in cycle 3,

and there were comparable reductions in total and phospho-BTK (Tyr223) protein

levels across the 3 cycles. Reductions of plasma chemokine CCL3 and CCL4 levels,

considered to be biomarkers of ibrutinib response, were similar over the 3 cycles.

These pharmacokinetics and pharmacodynamics data demonstrate that follow-

ing one cycle of ibrutinib at the standard 420mg/d dose, the dose can be reduced

without losing biological activity. Real-world experiences (Four different studies

in US, UK, Poland and Sweden) with ibrutinib further support this notion; no dif-

ference in progression free or overall survival between patients that had ibrutinib

dose reductions and those that did not. In conclusion, their investigations pro-

vide a scientific basis for dose-reduction which should be tested in a prospective

randomized trial. Such dose reductions would lower drug cost, lessen untoward

toxicity, and facilitate rationale-based combinations.

Varsha Gandhi, Hematol Blood Disord 2019, Volume 2

Varsha Gandhi is interim Chair for the Depart-

ment of Experimental Therapeutics at The Uni-

versity of Texas MD Anderson Cancer Centre in

Houston, Texas. She is also Professor and Rebecca

Meyer Brown and Joseph Mellinger Brown Chair

in Basic Science Research in the Department of

Experimental Therapeutics. She has published

more than 300 articles and serves as Associate Ed-

itor or Board Member of Clinical Cancer Research,

Leukemia and Lymphoma. She designed and de-

veloped a new graduate education program “Ex-

perimental Therapeutics” which is now offered

as Therapeutics and Pharmacology program at

the Graduate School of Biomedical Science. She

has several investigator-initiated peer-reviewed

grant supports from NIH, Leukemia and Lympho-

ma Society and CLL Global Research Foundation

and sponsored research agreements from Abb-

Vie, Loxo Oncology and Sunesis.

vgandhi@mdanderson.org

Varsha Gandhi

University of Texas MD Anderson Cancer Centre, USA

BIOGRAPHY