Arzerra (Ofatumumab) Receives FDA Approval for Patients with Previously Untreated Chronic Lymphocytic Leukemia for Use in Combination with Chlorambucil

Lisa A. Raedler, PhD, RPh

October 2014, Vol 4, No 6 - Drug Update

Chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults, is a cancer that predominantly affects the B-cell lymphocytes.1 Normal B-cell lymphocytes originate in the bone marrow, develop in the lymph nodes, and fight infection by producing an immune response.1 In CLL, excess B-cells accumulate in the bone marrow and blood, where they crowd out healthy blood cells.2

According to the Leukemia & Lymphoma Society, more than 15,600 Americans were diagnosed with CLL in 2013.3 The incidence of CLL increases significantly among people aged ≥50 years; only a small fraction of adults are diagnosed in their 30s and 40s.3 Most patients with CLL are asymptomatic and learn they have the disease as a result of a routine physical examination or a blood test.4 As CLL advances, patients can experience enlarged lymph nodes and an enlarged spleen, abnormal bleeding, and infections.5

According to the American Society of Clinical Oncology, the prognosis for patients with CLL varies significantly based on disease subtype and risk status, with survival ranging from approximately 1 year to more than 20 years.6 The 5-year overall survival rate for patients with CLL of all stages is approximately 79%.6

The cost burden associated with CLL is significant. A recent cost analysis conducted in Germany using the direct and indirect costs of CLL calculated the total per-patient cost to be approximately $13,500 annually compared with approximately $6600 annually for patients in an age- and sex-matched control group.7

The economic burden of CLL was primarily driven by inpatient and pharmaceutical costs in this study. From a societal perspective, productivity loss was the highest cost associated with a diagnosis of CLL.7

Patients with early-stage CLL are typically not treated, whereas patients with symptomatic intermediate- and high-risk CLL usually receive chemotherapy combined with a monoclonal antibody–targeting CD20.2 Studies comparing chemotherapy, such as fludarabine or the combination of fludarabine and cyclophosphamide, with immunotherapy (ie, rituximab in treatment-naïve patients with CLL) have shown that the rituximab-containing combinations significantly improve complete response rates, remission duration, and overall survival in CLL.2

Bendamustine is indicated as a single agent for the treatment of CLL.8 Studies of bendamustine combined with rituximab have demonstrated promising results in untreated and in previously treated patients with CLL.2

No consensus exists regarding the management of patients with relapsed or refractory CLL. Treatment decisions are based on several factors, including the timing of relapse, patient age, disease extent, overall health, and previous therapies.9 Drugs that are frequently used in the relapsed/refractory CLL setting (either alone or in combination) include bendamustine, chlor­ambucil, fludarabine, ofatumumab, and rituximab.9

The development of drugs for the treatment of CLL has been fruitful, with the US Food and Drug Administration (FDA) recently approving 3 new therapies. In November 2013, the FDA approved obinutuzumab in combination with chlorambucil for the treatment of patients with previously untreated CLL.10 Obinutuzumab is a humanized monoclonal antibody that targets CD20 on the surface of CLL cells.11

Ibrutinib was approved by the FDA in February 2014 for patients with CLL who have received at least 1 previous therapy.12 Ibrutinib is the first drug designed to target Bruton’s tyrosine kinase, a protein necessary for the growth and survival of malignant B-cells.13

In July 2014, the FDA approved idelalisib in combination with rituximab for patients with relapsed CLL for whom rituximab alone would be considered appropriate therapy, as well as for patients with relapsed follicular B-cell non-Hodgkin lymphoma and small lymphocytic lymphoma who have received at least 2 previous systemic therapies.14 Idelalisib inhibits PI3K delta, a protein that is overexpressed in many B-cell cancers. PI3K delta affects the viability, proliferation, and migration of malignant B-cells.12

FDA Approves Expanded Indication for Ofatumumab

On April 17, 2014, the FDA expanded the approved indications for ofatumumab (Arzerra; Glaxo­SmithKline), an anti-CD20 monoclonal antibody, for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom flu­darabine-based therapy is considered inappropriate.15 Ofatumumab was initially approved in 2009 for the treatment of patients with CLL that is refractory to fludarabine or to alemtuzumab.16

The FDA approved this new indication for ofatumumab based on a multicenter, randomized, open-label, parallel-arm trial of 447 patients with CLL for whom fludarabine-based therapy was deemed inappropriate based on the patient’s age and/or comorbidities.15 The ­primary end point of this trial was progression-free survival (PFS) as assessed by a blinded Independent Review Committee (IRC).15

The results of this randomized clinical trial fulfilled the postmarketing requirement by the FDA for the man­ufacturer to verify ofatumumab’s clinical benefit in patients with CLL. Consequently, the approval of the new indication for ofatumumab was converted from accelerated approval to regular process approval.17

Mechanism of Action

Ofatumumab binds to extracellular loops of the CD20 molecule, which is expressed on normal B lymphocytes and on B-cell CLL cells. After ofatumumab binds to the CD20 molecule, the Fc domain of the antibody mediates immune effector functions that result in cell lysis in vitro. Complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity are possible mechanisms of cell lysis that occurs after ofatumumab binding.16

Dosing and Administration

In patients with previously untreated CLL, the recommended dosage and schedule of ofatumumab is 300 mg on day 1, followed by 1000 mg on day 8 of the first 28-day cycle, followed by 1000 mg on day 1 of subsequent 28-day cycles. Treatment should be administered for a minimum of 3 cycles until best response or a maximum of 12 cycles.16 In the phase 3 study of ofatumumab in combination with chlorambucil, the oral agent was given at a dose of 10 mg/m2 on days 1 to 7 of the 28-day cycle.16

Patients receiving ofatumumab should be premedicated with acetaminophen, an antihistamine, and ­a corticosteroid. Infusion facilities should be adequately equipped to monitor and treat infusion reactions.16

During the first infusion of ofatumumab (cycle 1, day 1, 300-mg dose), the rate of infusion should be initiated at 3.6 mg per hour (12 mL per hour). The cycle 1, day 8, and subsequent infusions (cycles 2-12, 1000-mg dose) can be initiated at a rate of 25 mg per hour.16

If no infusion-related adverse events are observed, the rate of ofatumumab infusion can be increased every 30 minutes (Table 1).16 If a grade ≥3 infusion-related event was experienced during the previous administration of ofatumumab, the initial rate of infusion should decrease to 12 mg per hour (12 mL per hour).16

Table 1

Pivotal Phase 3 Clinical Trial

The safety and efficacy of ofatumumab in patients with previously untreated CLL were demonstrated in a phase 3 open-label, multicenter clinical trial known as COMPLEMENT 1. In this trial, 447 patients with CLL who were deemed unfit for fludarabine-based therapy were randomized to receive chlorambucil alone (N = 226) or ofatumumab combined with chlorambucil (N = 221).18

Chlorambucil was given orally at a dose of 10 mg/m2 on days 1 to 7 every 28 days in both arms of this study. Ofatumumab was administered as an intravenous infusion every month (first 28-day cycle: 300 mg on day 1 and 1000 mg on day 8; subsequent 28-day cycles: 1000 mg on day 1). In this trial, approximately 60% of the patients with CLL received 3 to 6 cycles of ofatumumab and 30% received 7 to 12 treatment cycles.18

The primary end point of this phase 3 study was PFS as assessed by a blinded IRC using the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) update of the National Cancer Institute Working Group guidelines. Secondary efficacy end points, which included overall response rate, complete response rate, and duration of response, were also assessed by the IRC using the 2008 IWCLL guidelines.18

Patient Population
Patients with previously untreated CLL who enrolled in the phase 3 clinical trial comparing ofatumu­mab plus chlorambucil with chlorambucil alone were considered by the investigators to be inappropriate for fludarabine-­based therapy for reasons that included advanced age and the presence of comorbidities.18

The median age of the population studied was 69 years, with the majority (69%) of patients in both arms aged ≥65 years.16,18 The study enrollees were mostly male (63%) and white (89%) and had 2 or more comorbidities (72%).15,18 A total of 48% of the patients had a creatinine clearance of <70 mL/min.16 Beta-2 microglobulin was elevated (>3500 mcg/L) in 72% of patients at baseline.18

Efficacy and Safety
In this phase 3 clinical trial, the combination of ofatumumab and chlorambucil in previously untreated patients with CLL resulted in a statistically significant improvement in IRC-assessed median PFS compared with chlorambucil alone (22.4 months vs 13.1 months, respectively).18 These data and results of secondary end point analyses are summarized in Table 2.16,18

Table 2

A total of 217 previously untreated CLL patients received ofatumumab combined with chlorambucil and 227 patients received chlorambucil alone.17 Overall, grade ≥3 neutropenia was observed in 26% of patients receiving the combination of ofatumumab plus chlorambucil compared with 14% in patients receiving chlorambucil alone; grade ≥3 infusion-related events were 10% in the combination group and were not available for the chemotherapy alone; grade ≥3 infections were similar between the 2 groups—15% with the combination versus 14% with chlorambucil alone.17

Adverse Reactions

Infusion Reactions
Overall, 67% of the patients who received ofatumumab plus chlorambucil experienced ≥1 infusion reactions, with 10% of patients experiencing reactions of grade ≥3 severity.16 None of these events was fatal.16

In the phase 3 clinical trial, the term “infusion reaction” encompassed events that occurred on the day of or within 24 hours of the end of an ofatumumab infusion and resulted in interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria.16

Severe infusion reactions (grade ≥3) or infusion reactions that led to treatment interruption or discontinuation occurred most frequently during the first cycle of ofatumumab (56% on day 1 and 23% on day 8).16 The rates of reactions decreased with subsequent infusions.16 Infusion reactions led to the discontinuation of treatment in 3% of the patients.16

The most common grade 3 or 4 hematologic adverse reactions associated with ofatumumab combined with chlorambucil included neutropenia (29%), lymphopenia (29%), and leukopenia (23%).16 Neutropenia occurring up to 60 days after the last dose of ofatumumab was reported as a serious adverse event in 3% of patients.16 One of these patients died as a result of neutropenic sepsis and agranulocytosis.16 Prolonged neutropenia was observed in 6% of patients receiving ofatumumab plus chlorambucil versus in 4% of patients receiving chlor­ambucil alone.16 Late-onset neutropenia occurred in 6% of patients receiving ofatumumab plus chlorambucil versus in 1% of patients receiving chlorambucil alone.16

Warnings and Precautions

Ofatumumab has no contraindications.

Boxed warning
Ofatumumab carries a boxed warning regarding the risk for hepatitis B virus (HBV) infection reactivation.16 High-risk patients should be screened for HBV infection before initiating ofatumumab therapy. HBV carriers should be monitored for signs of active infection during and after treatment with ofatumumab. In addition, progressive multifocal leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab.16

Infusion reactions
Ofatumumab can cause serious, including fatal, infusion reactions that manifest as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (eg, myocardial ischemia or infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid or anaphylactic reactions.16

Patients receiving ofatumumab should be premedicated with acetaminophen, an antihistamine, and a corticosteroid. However, infusion reactions can occur despite premedication.16 Treatment interruption or discontinuation may be required.16

The administration of ofatumumab should cease if infusion reactions of any severity are observed.16 Medical management for severe infusion reactions, including angina or other signs and symptoms of myocardial ischemia, should be instituted. If anaphylaxis occurs, ofatumumab should be discontinued immediately and permanently, and appropriate medical treatment should be initiated.16

HBV reactivation
HBV infection reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or the detection of HBV surface antigen (HBsAg) in a person who was previously HBsAg negative and hepatitis B core antibody (anti-HBc) positive. HBV reactivation is often followed by hepatitis B (ie, increased transaminase levels). Severe cases of reactivation can be followed by increased bilirubin levels, liver failure, and death.16

HBV reactivation has occurred in patients receiving ofatumumab, with some cases resulting in hepatitis, liver failure, or death.16 Cases have been reported in patients who are HBsAg positive, as well as patients who are HBsAg negative but anti-HBc positive. Reactivation also has occurred in patients who appeared to have resolved HBV infection.16

All patients for whom ofatumu­mab is being considered should be screened for HBV infection before the initiation of treatment.16 Patients with evidence of HBV infection should consult with physicians who have expertise in managing HBV to discuss the monitoring and potential use of HBV antiviral therapy.16

Patients with evidence of current or previous HBV infection should be evaluated for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months after treatment with ofatumumab. HBV reactivation has been reported for at least 12 months after the completion of therapy.16

If patients develop HBV reactivation during treatment with ofatumumab, the agent (and any concomitant chemotherapy) should be discontinued. Appropriate treatment should be instituted.16 Data regarding the safety of resuming ofatu­mumab in patients who develop HBV reactivation are insufficient.16

HBV infection
Fatal HBV infection has been documented with ofatumumab in patients who had not been previously infected.16 Patients with clinical and laboratory signs of hepatitis should be monitored.16

Progressive multifocal leuko­encephalopathy
Death resulting from PML has occurred with ofatumu­mab.16 PML should be considered in any patient describing the onset of or changes in preexisting neurologic signs or symptoms. If PML is suspected, ofatu­mumab should be discontin­ued. Evaluation for PML, including neurology consultation, should ­be initiated.16

Tumor lysis syndrome
Patients receiving ofatumumab have experienced tumor lysis syndrome (TLS), which has resulted in hospitalization.16 Patients who are at greater risk of TLS include those with high tumor burden and/or high circulating lymphocyte counts (>25 × 109/L).16 Prophylaxis of TLS using antihyperuricemic agents and hy­dration beginning 12 hours to 24 hours before the infusion of ofatumumab should be considered.16 The management of TLS includes aggressive intravenous hydration and antihyperuricemic agents, correction of electrolyte abnormalities, and renal function monitoring.16

Severe cytopenias can occur with ofatumumab, including neutropenia, thrombocytopenia,­ and anemia. Patients who received ofatumumab combined with chlorambucil have experienced pancytopenia, agranulocytosis, and fatal neutropenic sepsis.16

Patients receiving ofatumumab also experienced grade 3 or 4 late-­onset neutropenia, occurring at least 42 days after the last dose, and/or prolonged neutropenia that does not resolve between 24 and 42 days after the last dose.16

Complete blood count (CBC) should be monitored at regular intervals during and after the conclusion of therapy with ofatumu­mab. The frequency of CBC monitoring should increase in patients who develop severe cytopenias.16

There are no studies evaluating the safety of immunization with live viral vaccines in association with ofatumu­mab.16 Live viral vaccines should not be administered to patients who have recently received ofatumumab.

Specific Populations

Ofatumumab has been assigned pregnancy Category C.16 There are no adequate or well-controlled studies of ofatumumab in pregnant women.16 Ofatumumab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.16 Caution should be exercised when administering the drug to a nursing woman.16

The safety and efficacy of ofatumumab in pediatric patients have not been established.16

In the clinical trial of previously untreated patients with CLL, 148 (68%) of the 217 patients receiving ofatumumab plus chlorambucil were aged ≥65 years.16 Patients aged ≥65 years were more likely to experience specific grade ≥3 adverse reactions compared with young patients, especially neutropenia (30% vs 17%, respectively) and pneumonia (5% vs 1%, respectively). In patients aged ≥65 years, 29% experienced serious adverse events compared with 13% of young patients. No significant differences in the effectiveness of the combination of ofatumumab and chlor­ambucil were observed between older and younger patients with previously untreated CLL.16


The addition of ofatumumab to chlorambucil represents a clinically meaningful improvement, with manageable side effects, for the treatment of previously untreated patients with CLL who are deemed inappropriate to receive fludarabine therapy. This doublet has demonstrated improved PFS in this patient population with limited therapeutic options. The safety and efficacy of ofatumumab combined with other agents for the treatment of CLL and other hematologic malignancies are being explored.19 Examples include a trial combining ofatumumab and ibrutinib for patients with relapsed or refractory CLL, and a trial combining idelalisib with ofatumumab in patients with previously untreated CLL or small lymphocytic lymphoma.19


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