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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
YEARS
4th 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.
Varsha Gandhi
University of Texas MD Anderson Cancer Centre, USA
BIOGRAPHY