Paul Barr, MD: Dose Intensity

What is the importance of achieving good dose intensity in this patient?

It is important to achieve an adequate dose intensity or dose adherence using ibrutinib in such a patient. The data supporting this come from a post hoc analysis where we analyzed patients enrolled to the Resonate trial who were treated with ibrutinib. The mean dose intensity, or another way to think of that is the dose given over the course of the trial, was 95% for ibrutinib, which  speaks volumes about the efficacy and  tolerability of the drug.  Nonetheless, we compared patients who had a dose intensity above the mean and below the mean and found [that patients with] the better dose intensity had an improved PFS, suggesting that you need to stay on the drug to get the benefit.

It’s important to point out that there are good reasons to hold ibrutinib: severe side effects such as bleeding, planned surgical procedures, use of medications that interact with ibrutinib. Those are all good reasons the drug should be held, but it’s equally important to return to full-dose intensity in a timely manner.

Case 1: Relapsed and Refractory CLL

Robert is a 63-year-old retired civil engineer from Houston, Texas. His medical history is notable for mild hypertension and for an acute appendicitis and appendectomy in 2010. He presented to his PCP in September 2012 with symptoms of intermittent fatigue and abdominal discomfort.

On physical examination, Robert showed moderate splenomegaly (12 cm), lymphadenopathy, and CBC showed elevated WBC count of 98 x 109/L, with 80% lymphocytes, and anemia (Hb 11 g/dL).

He was referred to an oncologist for further evaluation and was subsequently diagnosed with (CLL); peripheral blood flow cytometry showed mature B lymphocytes CD5+/CD23+.

Interphase cytogenetic analysis showed 17p13.1 deletion

He was initiated on chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) in October 2012

After 5 cycles he displayed a complete response, with disappearance of palpable disease, normalization of blood counts, and no evidence of disease on bone marrow biopsy and CT scans.

In January 2015, he presented to his oncologist with symptoms of worsening fatigue and abdominal distension.

• On relapse he shows bulky disease 5.5 cm; Hb 12 g/dL, platelets 120,000 cells/mm3, lymphocytes 39,000/mm3, and beta 2 microglobulin of 4.1 mg/L
• His ECOG performance status at the time of recurrence was 1, and liver and kidney function were within normal limits