A Phase II Trial Evaluating the Safety of Rapid Infusion of Ofatumumab in Patients with Previously Treated Chronic Lymphocytic Leukemia.

LESSONS LEARNED: Ofatumumab infusion reactions can be diminished by escalating the dose rate in individual patients in sequential infusions.
BACKGROUND: Ofatumumab (OFA) is a fully humanized, anti-CD20 antibody approved for use in chronic lymphocytic leukemia (CLL). The recommended administration requires long infusion times. We evaluated an accelerated infusion regimen of 2 hours.
METHODS: The first dose of OFA (300 mg) was given on week 1 day 1 starting at 3.6 mg/hour and doubling every 30 minutes until a rate of 240 mg/hour was reached. If tolerated, the second dose (1,000 mg) was given on week 1 day 3 starting at 50 mg/hour and doubling every 30 minutes until a rate of 800 mg/hour was reached. If tolerated, the third dose (2,000 mg) was given on week 2 day 1 at 800 mg/hour over the first 30 minutes and, if tolerated, at 1,068 mg/hour over the next 90 minutes (goal infusion time: 120 minutes). Subsequent OFA infusions were administered weekly in the same manner for 8 weeks, and then monthly for 4 months.
RESULTS: Thirty-four patients were treated. Most infusion-related reactions occurred during the first and second infusion. Eighty-seven percent (87%) of patients finished the third infusion within 15 minutes of the planned 2 hours and only one had an infusion reaction.
CONCLUSION: Using this stepped-up dosing regimen, a rapid infusion of OFA is safe and well tolerated. ©AlphaMedPress; the data published online to support this summary is the property of the authors.

Discussion

Ofatumumab, obinutuzumab, and rituximab are all effective anti‐CD20 monoclonal antibodies that can cause side effects during or after infusion. However, previous studies using rituximab show that infusion‐related reactions can be overcome by first starting with a lower dose and then giving a second larger dose within a few days of the initial dose. Such an approach allows for the rapid infusion of rituximab in subsequent doses in patients with CLL. Our completed phase II study of ofatumumab in patients with CLL clearly corroborates the feasibility of reducing the frequency of infusion‐related reactions by using this same approach. As shown in Table 1 and Table 2, the number of patients with CLL that experienced infusion‐related reactions steadily decreased at each infusion (infusion 1: 62%; infusion 2: 12%, and infusion 3: 3%). These results underscore that our study design was successful and appropriate for the 97% of patients with CLL who completed infusion 3 and, of those, the 87% who completed infusion 3 within the 2‐hour treatment plan.

Table 1.

Summary of ofatumumab infusion times

Table 2.

Infusion‐related toxicities

Abbreviation: —, no occurrence.

A stepped‐up dosing schedule of ofatumumab has implications that go beyond minimizing infusion‐related reactions and avoiding wasted medication; it also addresses quality‐of‐life concerns. The less time that patients spend in the oncologist's office equates to more time that patients can spend doing more pleasurable activities.

Trial Information

Leukemia – chronic – CLL

Metastatic/advanced

One prior regimen

Phase II

Single arm

Deliverability

Safety

Objective response rate

Toxicity

Progression‐free survival

Active and should be pursued further

Drug Information for Phase II Ofatumumab

Ofatumumab

Arzerra

Novartis and GlaxoSmithKline

Antibody

CD20

Infusion 1: 300 mg; infusion 2: 1,000 mg; infusion 3: 2,000 mg milligrams (mg) per flat dose

IV

Patient Characteristics for Phase II Ofatumumab

17

17

Rai stage 0: 3 (9%)

Rai stage 1: 8 (23%)

Rai stage 2: 7 (21%)

Rai stage 3: 4 (12%)

Rai stage 4: 11 (32%)

Unknown: 1 (3%)

Median (range): 70 (53–89)

Median (range): 1 (1–5)

9 (26%)

18 (53%)

7 (21%)

13 (38%)

18 (53%)

3 (9%)

18 (53%)

5 (15%)

11 (32%)

8 (24%)

25 (73%)

8 (24%)

15 (44%)

6 (18%)

8 (24%)

1 (3%)

Chronic lymphocytic leukemia: 34

Chronic lymphocytic leukemia, poor risk: 13

Primary Assessment Method for Phase II Ofatumumab

13

12

12

International Workshop on CLL Working Group (IWCLL WG) diagnostic criteria

n = 0 (0%)

n = 0 (0%)

n = 11 (92%)

n = 1 (8%)

n = 1 (8%)

34

34

31

31

IWCLL WG diagnostic criteria

n = 0 (0%)

n = 6 (32%)

n = 11 (58%)

n = 2 (10%)

n = 2 (10%)

9.2485 months, CI: 95%

0 months, CI: 95%

Response Assessment Table

All patients,

6 (19%)

6 (19%)

22 (71%)

3 (10%)

3 (10%)

Adverse Events: Phase II Ofatumumab

Serious Adverse Events

Assessment, Analysis, and Discussion

Study completed

Active and should be pursued further

The anti‐CD20 antibodies, either alone or in combination, have become an integral part of the treatment of patients with B‐cell lymphomas and chronic lymphocytic leukemia (CLL). However, infusions of the antibodies can be difficult in patients with CLL due to an increase in infusion reactions such as fever and hypotension. The observation with rituximab that these reactions are generally worse on the first infusion than on subsequent doses has led to the development of alternative dosing regimens in CLL.

Ofatumumab (OFA) is a fully human anti‐CD20 antibody that induces B‐cell lysis primarily through complement‐dependent cytotoxicity (CDC) and antibody‐dependent cell‐mediated cytotoxicity [1]. It recognizes a different epitope of the CD20 molecule than rituximab [2], [3]. Ofatumumab was found to be effective in the pivotal GSK 406 study of 223 patients with CLL [4]. Interestingly, ≥90% of patients in the GSK 406 study did not have significant infusion‐related reactions following the second OFA dose. Furthermore, the majority of the reported infusion‐related reactions were Grade 1 or 2 and the median duration of the third dose was 4.3 hours (range 2.6–21.3). The GSK 406 data suggest that the infusion rate of OFA could be accelerated, which aligns with other trials using the anti‐CD20 antibody, rituximab [5], [6], [7].

While previous and ongoing studies report that OFA is safe, well tolerated, and has demonstrated significant activity in patients with CLL [4], [5], [6], [7], the issue for many patients and physicians is the 4‐hour infusion time. The purpose of this study was to evaluate an accelerated infusion regimen that allows the third OFA 2,000 mg infusion to be safely delivered over a 2‐hour time period to patients with CLL. We found that 87% of patients could complete the third dose (2,000 mg) within 2 hours, which was the primary endpoint of the study. It is important to note that the second dose of OFA was given 2 days after the first dose rather than the standard approach of giving it a week later. This schedule was chosen based on our previous experience of giving rituximab thrice weekly and the hypothesis that giving anti‐CD20 antibodies in close sequence increases tolerability by preventing rebound after the initial infusion [5].

Progression‐free survival.

Overall survival.

Adverse events account for all 34 patients.

Infusion‐related reactions: one patient, grade 3 dyspnea (infusion 1 and infusion 2)/facial flushing (infusion 1); one patient, grade 3 hives (infusion 1).

Abbreviation: NC/NA, no change from baseline/no adverse event.

Number of treatment related deaths: 0; number of related SAEs: 4.

Total number of patients with related SAEs: 3 (grade 3 SAEs, 1 patient each).

Abbreviation: SAE, serious adverse event.

Table 3.

Patient characteristics

Abbreviations: ALC, absolute lymphocytic count; OFA, ofatumumab.