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Real-World Ibrutinib Dose Reductions, Discontinuations in CLL

March 11, 2021


Jing-Zhou Hou, MD, PhD, University of Pittsburgh Medical Center, Hillman Cancer Center, PA, discusses results from a study comparing dose reductions and discontinuations between patients with chronic lymphocytic leukemia (CLL) receiving ibrutinib in community and academic settings.

These results were presented at the virtual 2020 ASH Annual Meeting.


I'm Jing‑Zhou Hou, a physician in hematology and bone marrow transplant at the UPMC Hillman Cancer Center, and my primary clinical research is on non‑Hodgkin's lymphoma. Today, I will share our study on CLL.

As we know, Bruton's tyrosine kinase inhibitor has replaced chemoimmunotherapy as the standard of care for patients with CLL in both a frontline setting and the relapse setting. The side effects of the BTK inhibitors has become more aware and relatively common as we use more in the general population.

In the initial phase 3 trials with the BTK inhibitor, particularly with ibrutinib, which is the first one approved in the class, the reported side effects in the clinical trial was around 5-10% or 4-9%. There is a few real‑world analysis show that CLL patients probably have higher AE, or adverse events, on the BTK inhibitor, or ibrutinib, somewhere between 14-23%.

Similarly, reported dose reduction due to the AEs in a real‑world setting has been higher than initially reported, which was around 9%.

Most patients with CLL are treated in the community practice, about 90% are treated in the community practice. Therefore, our study tried to compare with the real‑world data for a patient taking ibrutinib in the real‑world setting.

In our study, we have three institutions. One is the academic centers at the UPMC Hillman Cancer Center in Pittsburgh. In addition, we have two community sites. One is in New Jersey, one is in Oklahoma. Totally, we have 180 patients included in this study, 80 patients from the Human Cancer Center and 50 patients from each of the two community sites.

We look at the patients being treated on ibrutinib since the beginning of 2014 and March 1, 2014, until June 30, 2019, so cutoff over the course of 5 years. The patients included in this study, both in the CLL in the frontline as well in the relapse setting.

The criteria for this inclusion for the study were patients at least have been on the ibrutinib for six months between the index date and end of the study period. Also, the participants on the clinical trial were excluded from this study.

Overall, we see that 56% in the community setting, and the patient at the baseline, the median age of patient is 69.5 years old. In the frontline setting, it's 70.5 years old. In the relapse refractory setting, the median age of the patient is 68 years old.

As we know, there is gender preference of CLL. For men, we see a little bit more in our study as well. We have 65% patients are men, and 34.4% are women, at the baseline of the patient that has significant comorbidity in the real‑world setting, as we normally see.

They're including 14% patients with atrial fibrillation really controlled before they started this ibrutinib. They also have the 1% patient prior history of bleeding, and also, we have 8.9% of patients with a history of full congestive heart failure.

In addition, this patient population has taken other medications for their cardiac comorbidity. Particularly, 10% of people anticoagulation because of atrial fibrillation, and also have patient have antiplatelet agent, about 23% of people taking antiplatelet agent because of their cardiac history. Also, 7.8% are taking anti-arrhythmia drug for their atrial fibrillation.

The median number of prior therapy for CLL is one, with a range of 0-4. We also have FISH and cytogenetic studies or a report available from this whole cohort.

Overall, we see we have 18.3% patient with 17p deletions. We also have a 17.2% patient with 11q abnormalities, and 36% with 13q abnormalities. The initial patient at the full dose, which is 400 mg, is about 89%. We have another 11% of people start at a lower dose.

A majority of patients—I'll say 91.7%—have been patients treated with a monotherapy from the ibrutinib, and no rituxan or monoclonal antibody was combined.

The median follow‑up of the months in this analysis is 28 months. The shortest one is 6 months, and the longest one is 62.3 months.

From this study, in the frontline setting we see a dose reduction of 20%. The majority of the dose reduction is due to the AEs, and we see about 79% due to the AEs. The common AE, including GI toxicities and atrial fibrillation and bleeding.

For the dose discontinuation, we see around 14% patients in the frontline setting with dose discontinuation due to AEs. The overall dose discontinuation, or drug discontinuation, around 20%. In the relapse setting, the incidence of dose reduction and drug discontinuation is much higher.

In overall, the dose reduction is around 27%, and 24% are due to the dose reduction. The drug discontinuation, or dose discontinuation, is much higher with around 40%. Out of the 40%, we see about 76% due to the AEs. A second common cause of the discontinuation of drug is the progression of the disease, where a small number of patients discontinue the treatment due to the financial burdens.

When we look at further in‑depth details, the common AEs is those cohort, including GI toxicities, atrial fibrillation, and we also see 12% of patients has a significant infection episode.

Fatigue is not a common side effect, overall at around 24%, and a decreased appetite. Now, joint pain is another relatively common side effect, which we'll see around 20% of patients. We also have 5% of patients with bruising, and we see a 7% of patients with a rash.

We also see a lot of patients with hypertension, but the overall is not too high. We see 2% of patients with new onset of hypertension or worsening hypertension. I look further, when attempt to discontinuation, overall, it's about 10 months. In the community setting, we see 10 months. In the academic setting, also 10 months.

The time to discontinuity due to AEs is a little bit shorter. In academia, around 7 months. In the community, we see the median time to discontinuation due to AEs is 3 months.

The time to discontinuity due to progression or refractory disease is overall very similar, at around 30 months. In academia, we see 31 months. In the community, we see 29 months. We also see the time to first‑dose reduction is about 4 months in both academia setting and the community setting.

In summary, the dose discontinuation or reduction was relatively frequent, actually quite frequent, in the real‑world CLL patient than the initial report on phase 3 clinical trials. The common reason for discontinuation or dose reduction, really, due to the AEs, they're including GI side effects and atrial fibrillation and arthralgia.

The rate of discontinuation or reduction due to AEs in our study was higher, and we also compare with other published real‑world studies, and it's comparable. However, this study is limited by a smaller size. We had a total of over 180 patients, and also this study is a retrospective analysis. We review the medical record, so this is the other major limitations.

Thank you.

Hou JZ, Ryan K, Du S, et al. Dose Reductions and Discontinuations with Chronic Lymphocytic Leukemia (CLL) Patients Receiving Ibrutinib in Community and Academic Settings. Presented at: the 62nd ASH Annual Meeting and Exposition; Dec 5-8, 2020. Abstract 905.   

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