Outcomes in patients with comorbidities treated with ublituximab + umbralisib: a UNITY CLL retrospective analysis

The advanced age of most patients with chronic lymphocytic leukemia (CLL)—a disease for which the median age at diagnosis is 70 years—complicates its management; many of these patients have comorbidities and are on multiple other medications, which must be considered when selecting treatment. Traditional chemotherapy regimens may be intolerable for elderly patients with comorbidities and even newer targeted therapies may not be the best choice for certain patients. The adverse event (AE) profile of Bruton’s tyrosine kinase (BTK) inhibitors, for example, is such that it may be risky for patients with a history of cardiovascular or bleeding issues, and continuous treatment may be interrupted in patients with hypertension, potentially compromising the therapeutic effect of the drug.¹

At the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, Pinilla-Ibarz, et al. presented a poster with data from a retrospective analysis of the phase 3 UNITY-CLL trial (NCT02612311), which compared the novel anti-CD20 monoclonal antibody ublituximab + the phosphoinositide 3-kinase delta (PI3Kδ) inhibitor umbralisib (U2) with obinutuzumab + chlorambucil in patients with untreated and previously treated CLL. The analysis, which was conducted in patients treated with U2 who had a pre-existing comorbid condition or concomitant medication that could preclude treatment with BTK inhibitors, is summarized below.¹

Study design

In the UNITY-CLL trial, previously treated and treatment-naïve patients with CLL were randomized 1:1:1:1 to U2, obinutuzumab + chlorambucil, umbralisib monotherapy, or ublituximab monotherapy. Eligibility criteria included age ≥18 years, adequate organ function, and Eastern Cooperative Oncology Group Performance Status score ≤2. More detailed information on the design of the UNITY-CLL trial can be found here.

Baseline characteristics

Patients included in the retrospective analysis had a pre-existing comorbidity or concomitant medication that could potentially preclude treatment with a BTK inhibitor. Pre-existing cardiac or bleeding issues, hypertension, and history of autoimmune disease are potential risk factors for adverse events associated with BTKi therapy (Table 1).

Table 1. Comorbid conditions in UNITY-CLL patients who received U2*

U2, ublituximab and umbralisib. *Adapted from Pinilla-Ibarz, et al.1
Comorbidities, n (%)	U2 population
Arrythmia	31 (15)
Hypertension and 2 antihypertensives	45 (22)
Cardiovascular dysfunction (myocardial infarction, coronary artery disease, myocardial ischemia, etc.)	50 (24)
History of hemorrhage	5 (2)
Arthritis/arthralgia	46 (22)
Unique patients	114 (55)

Regarding concomitant medications, currently available BTKi have shown drug-drug interactions with CYP3A inhibitors and inducers and proton pump inhibitors, and anticoagulant/antiplatelet therapy increases the risk of major hemorrhage when taken concomitantly with BTKi (Table 2).

Table 2. Concomitant medications in UNITY-CLL patients who received U2*

PPI, proton pump inhibitor; U2, ublituximab and umbralisib. *Adapted from Pinilla-Ibarz, et al.1
Concomitant medications, n (%)	U2 population
Anticoagulant	9 (4)
CYP3A4 moderate inhibitor	7 (3)
CYP3A4 strong inducer	2 (1)
CYP3A4 strong inhibitor	1 (0.5)
Dual antiplatelet or anticoagulant	2 (1)
Polypharmacy	5 (2)
PPI	37 (18)
Vitamin K antagonist	2 (1)
Unique patients	53 (26)

Results

There were 206 patients in the UNITY-CLL study who received treatment with U2, and of those, 131 (63.6%) met at least one BTKi risk factor criteria (as outlined in the tables above). Among the patients who met at least one risk factor for BTKi treatment, the median age was 69 years (slightly higher than the 67-year median age in the overall cohort). Other disease characteristics were similar to those seen in the overall cohort:

• 11% of patients with a BTKi risk factor had del(17)p;
• 56% were IgHV unmutated; and
• 57% were treatment naïve.

At a median follow-up of 36.7 months, 40% of patients with a BTKi risk factor remain on treatment with U2 vs 37% in the entire U2 treated population. The median progression free survival for patients with a BTKi risk factor was 31.9 months, which was equivalent to the entire U2-treated population, and the overall response rate was slightly higher but not significantly so (88% vs 83%).

Comorbidities and concomitant medications did not increase discontinuation rates in patients receiving U2, discontinuations due to AEs and deaths did not appear to be exacerbated by comorbidities or concomitant medications. There were no significant differences in the incidences of serious AEs or Grade ≥3 AEs (Table 3).

Table 3. UNITY-CLL safety overview*

AE, adverse event; con med, concomitant medication; U2, ublituximab and umbralisib. †Fatal AEs on U2 included glioblastoma, neutropenic sepsis, sepsis, sudden cardiac death, cardiac arrest, acute myocardial infarction, progressive multifocal leukoencephalopathy, and pneumonia. *Adapted from Pinilla-Ibarz, et al.1
AE, % (unless otherwise stated)	Entire U2 population (N = 206)	No comorbidity or con med (n = 75)	Any comorbidity or con med (n = 131)	≥1 comorbidity (n = 114)	≥1 con med (n = 53)
Median exposure, months
Umbralisib	21	21	18	19	21
Ublituximab	21	19	22	21	25
Patients with ≥1 AE	100	100	100	100	100
Serious AEs	46	39	50	49	59
Grade ≥3	82	80	83	82	85
Fatal AEs†	4	5	3	4	2

Conclusion

In this retrospective analysis, patients with at least one BTKi risk factor (thus potentially rendering BTKi therapy unsuitable) who were treated with U2 demonstrated similar efficacy results to those seen in the general population of patients treated with U2 in the UNITY-CLL trial. The comorbidities in these patients did not appear to significantly impact the safety of U2 as evidenced by discontinuation rates similar to that of the overall population.