Ofatumumab (Arzerra)

Number: 0794

Policy

Aetna considers ofatumumab (Arzerra) medically necessary for the treatment of individuals with the following indications:

• Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) 
• Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma - when all of the following criteria are met:
  1. The disease is relapsed, refractory, or progressive, and
  2. The member is intolerant to rituximab.
• B-cell lymphomas, including AIDS-related B-cell lymphomas, Burkitt lymphoma, Castleman’s disease, diffuse large B-cell lymphoma, follicular lymphoma (FL), gastric or nongastric MALT lymphoma, high-grade B-cell lymphomas, histologic transformation of nodal marginal zone lymphoma to diffuse large B-cell lymphoma, mantle cell lymphoma, nodal marginal zone lymphoma, post-transplant lymphoproliferative disorders, and splenic marginal zone lymphoma - as a substitute for rituximab or obinutuzumab in members experiencing rare complications from rituximab or obinutuzumab such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis.

Aetna considers continuation of ofatumumab (Arzerra) medically necessary for a medically necessary indication, when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Aetna considers ofatumumab experimental and investigational for the treatment of the following indications (not an all inclusive list) because its effectiveness for these indications has not been established:

• Acute lymphoblastic leukemia (ALL)
• Autoimmune neutropenia
• Crohn's disease
• Focal segmental glomerulosclerosis
• Graft-versus-host disease
• Granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) 
• Hodgkin lymphoma
• Idiopathic thrombocytopenic purpura
• Lupus nephritis,
• Multiple sclerosis
• Nephropathy
• Nephrotic syndrome (including idiopathic nephrotic syndrome)
• Nephritic-nephrotic syndrome
• Paraneoplastic opsoclonus-myoclonus/opsoclonus-myoclonus syndrome
• Pemphigus vulgaris
• Rheumatoid arthritis
• Systemic lupus erythematosus
• Vasculitis (including ANCA-associated vasculitis)

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

Chronic lymphocytic leukemia (CLL):

• Arzerra is indicated in combination with chlorambucil, for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.
• Arzerra is indicated in combination with fludarabine and cyclophosphamide for the treatment of patients with relapsed CLL.
• Arzerra is indicated for extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL.
• Arzerra is indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab.

Compendial Uses

• CLL
• Small lymphocytic lymphoma (SLL) (managed in the same manner as CLL)
• Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma
• Follicular lymphoma. substitute for rituximab or obinutuzumab in patients experiencing rare complications from rituximab or obinutuzumab
• Gastric MALT lymphoma, substitute for rituximab or obinutuzumab in patients experiencing rare complications from rituximab or obinutuzumab
• Non-gastric MALT lymphoma, substitute for rituximab substitute for rituximab or obinutuzumab in patients experiencing rare complications from rituximab or obinutuzumab
• Nodal marginal zone lymphoma, substitute for rituximab or obinutuzumab in patients experiencing rare complications from rituximab or obinutuzumab
• Splenic marginal zone lymphoma, substitute for rituximab or obinutuzumab in patients experiencing rare complications from rituximab or obinutuzumab
• Histologic transformation of nodal marginal zone lymphoma to diffuse large B-cell lymphoma, substitute for rituximab or obinutuzumab in patients experiencing rare complications from rituximab or obinutuzumab
• Mantle cell lymphoma, substitute for rituximab or obinutuzumab in patients experiencing rare complications from rituximab or obinutuzumab
• Diffuse large B-cell lymphoma, substitute for rituximab or obinutuzumab in patients experiencing rare complications from rituximab or obinutuzumab
• High-grade B-cell lymphomas, substitute for rituximab or obinutuzumab in patients experiencing rare complications from rituximab or obinutuzumab
• Burkitt lymphoma, substitute for rituximab or obinutuzumab in patients experiencing rare complications from rituximab or obinutuzumab
• AIDS-related B-cell lymphomas, substitute for rituximab or obinutuzumab in patients experiencing rare complications from rituximab or obinutuzumab
• Post-transplant lymphoproliferative disorders, substitute for rituximab or obinutuzumab in patients experiencing rare complications from rituximab or obinutuzumab
• Castleman’s disease, substitute for rituximab or obinutuzumab in patients experiencing rare complications from rituximab or obinutuzumab.

Arzerra (ofatumumab) is an IgG1x human monoclonal antibody that binds specifically to both the small and large extracellular loops of the CD20 molecular. The CD20 molecule is expressed on normal B lymphocytes (pre-B to mature B-lymphocytes) and on B-cell CLL. The CD20 molecule is not shed from the cell surface and is not internalized following antibody binding. The Fab domain of ofatumumab binds to the CD20 molecule and the Fc domain mediates immune effector functions to result in B-cell lysis in vitro. Data suggest that possible mechanisms of cell lysis include complement-dependent cytotoxicity and antibody-dependent, cell-mediated cytotoxicity.

Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL), affecting primarily individuals aged 50 years or older, is a type of non-Hodgkin's lymphoma (NHL) that results from an accumulation of partially differentiated lymphocytes.  Each year, approximately 16,000 individuals are diagnosed with CLL in the United States, and about 4,400 succumb to the disease.  Chronic lymphocytic leukemia can affect the liver, spleen, and lymph nodes.  The disruption of normal lymphocyte production leaves patients with CLL vulnerable to infections; anemia and thrombocytopenia are also common complications.  Some CLL cells express a substance called ZAP-70, which is a marker for an aggressive form of CLL that is more likely to progress.  Treatments for lymphomas depend on the disease type, stage, and other prognostic markers.  Because certain lymphomas are categorized as indolent, "watchful waiting” is an option for some patients with follicular NHL or low-risk CLL.  Neither NHL nor CLL has been shown to be curable by any standard treatment.
 
The Guidelines Working Group of the United Kingdom CLL Forum/British Committee for Standards in Haematology's guidelines on the diagnosis and management of CLL (Oscier et al, 2004) noted that for the majority of patients who are ineligible for a transplant procedure and in whom there is no contraindication to fludarabine (e.g., severe renal impairment or an autoimmune cytopenia), both fludarabine and chlorambucil are therapeutic options.  Patients in whom fludarabine is contraindicated and for whom a palliative approach has been adopted should be treated with chlorambucil.  Moreover, there is no survival advantage for including an anthracycline with chlorambucil in the initial treatment of advanced CLL.  Montserrat (2006) stated that an important area of research in the prognosis of CLL is the identification of markers useful for predicting response to therapy and its duration.  Among them, del(17p), reflecting P53 abnormalities, is particularly important.  In this regard, Lindhagen and colleagues (2009) noted that cells from patients with unfavorable genomic aberrations [del(11q)/del(17p)] showed lower drug sensitivity to fludarabine and chlorambucil than cells from patients with favorable cytogenetics [del(13q)/no aberration].
 
Bosch et al (2008) examined fludarabine, cyclophosphamide, and mitoxantrone (FCM) as first-line therapy in CLL.  A total of 69 patients under the age of 65 years with active CLL were treated.  Patients received 6 cycles of fludarabine 25 mg/m(2) intravenous (IV) x 3 days, cyclophosphamide 200 mg/m(2) IV x 3 days, and mitoxantrone 6 mg/m(2) IV x 1 day.  Treatment outcome was correlated with clinical and biological variables.  The clinical significance of eradicating minimal residual disease (MRD) was also analyzed.  The overall response, MRD-negative complete response (CR), MRD-positive CR, nodular partial response (PR), and PR rates were 90 %, 26 %, 38 %, 14 %, and 12 %, respectively.  Severe (grades 3 or 4) neutropenia developed in 10 % of the patients.  Major and minor infections were reported in 1 % and 8 % of cases, respectively.  Median response duration was 37 months.  Patients with del(17p) failed to attain CR.  Patients achieving MRD-negative CR had a longer response duration and overall survival (OS) than patients with an inferior response.  Low serum lactate dehydrogenase levels, low ZAP-70 expression, and mutated IgV(H) genes predicted longer response duration.  Finally, both low ZAP-70 and CD38 expression in leukemic cells correlated with MRD-negativity achievement.  The authors concluded that FCM induces a high response rate, including MRD-negative CRs in untreated patients with active CLL.  Treatment toxicity is acceptable.  Both high ZAP-70 and increased CD38 expression predict failure to obtain MRD-negative response.  Patients in whom MRD can be eradicated have longer response duration and OS than those with inferior response. These results indicate that FCM can be an ideal companion for chemo-immunotherapy of patients with CLL.
 
The National Comprehensive Cancer Network (NCCN)'s Clinical Practice Guidelines in Oncology on NHL (2010) noted that the first line therapy for CLL without del(17p) include monotherapy (e.g., alemtuzumab, bendamustine, chlorambucil, fludarabine, and rituximab), purine-analog therapy (fludarabine, cyclophosphamide [FC]), chemo-immunotherapy (e.g., fludarabine, rituximab [FR]; fludarabine, cyclophosphamide, rituximab [FCR]; and pentostatin, cyclophosphamide, rituximab [PCR]), as well as alkylating agent-based chemotherapy (e.g., cyclophosphamide, prednisone and vincristine, [CPV]).  For CLL with del(17p) with greater than 20 % cells, the first-line therapy include alemtuzumab, CFAR (FCR + alemtuzumab), FR, FCR and high-dose methylprednisone plus rituximab (HDMP + R).
 
Christian and Lin (2008) stated that the introduction of rituximab (anti-CD20) and alemtuzumab (anti-CD52) has revolutionized the treatment of CLL.  Both antibodies were first studied as single agents in relapsed CLL, but rituximab is increasingly used in combination chemo-immunotherapy regimens in previously untreated patients.  Phase II studies demonstrated that the addition of rituximab to fludarabine-based chemotherapy improves CR rates and prolongs progression-free survival, but a long-term survival benefit has not been shown.  Alemtuzumab is less commonly used, due to the greater likelihood of infusion toxicity, as well as hematologic and immune toxicities.  Subcutaneous administration significantly reduces infusion toxicity, but hematologic and infectious complications, most notably cytomegalovirus reactivation, still occur with subcutaneous dosing.  Alemtuzumab's unique clinical properties include its clinical activity in relapsed CLL patients with del(17p13) and its ability to eradicate MRD in bone marrow.  Its use as consolidation therapy to eradicate MRD after nucleoside analog therapy is under active study.  Several investigational monoclonal antibodies are in pre-clinical or clinical studies, most notably lumiliximab and ofatumumab.
 
Ofatumumab (HuMax CD20) is a human anti-CD20 monoclonal antibody; CD20 is a transmembrane protein antigen that is expressed on B lymphocytes, from the pre-B-cell stage through the mature stage, but is not expressed on stem cells or plasma cells.  Anti-CD20 therapy thus specifically targets B-cells, and induces cell death through antibody dependent cellular cytotoxicity.  The first anti-CD20 antibody approved was rituximab (Rituxan), a chimeric mouse-human antibody that has been in use since 1997 and is now commonly used in the management of patients with NHL.  Ofatumumab is a fully human monoclonal antibody that may have the advantage of improved efficacy and pharmacokinetics with fewer adverse effects compared to chimeric antibodies.  Recent evidence suggested that a fully human anti-CD20 monoclonal antibody binds to unique epitopes on the CD20 antigen and appears to initiate cytotoxic processes not demonstrated by rituximab (Ingenix, 2009). 
 
In a phase I/II study, Coiffier et al (2008) analyzed the safety and effectiveness of ofatumumab in a multi-center dose-escalating study including 33 patients with relapsed or refractory CLL.  Three cohorts of 3 (A), 3 (B), and 27 (C) patients received 4, once-weekly, infusions of ofatumumab at the following doses: (A) one 100-mg and three 500-mg; (B) one 300-mg and three 1,000-mg; (C) one 500 mg and three 2,000-mg.  A total of 67 % of the patients were Binet stage B, and the median number of previous treatments was 3.  The MTD was not reached.  The majority of related adverse events occurred at first infusion, and the number of adverse events decreased at each subsequent infusion.  Seventeen (51 %) of 33 patients experienced infections, 88 % of them of grade 1 to 2.  One event of interstitial pneumonia was fatal; all other cases resolved within 1 month.  The response rate of cohort C was 50 % (13/26), 1 patient having a nodular partial remission and 12 patients partial remission.  The authors concluded that ofatumumab was found to be well-tolerated in patients with CLL in doses up to 2,000 mg.  Preliminary data on safety and objective response are encouraging and support further studies on the role of ofatumumab in CLL patients.  Furthermore, in a review on modern concepts in the treatment of CLL, Smolej (2009) noted that the monoclonal antibody anti-CD20 ofatumumab is currently undergoing clinical trials with promising results.

In a review on the use of ofatumumab for the treatment of B-cell malignancies, Cheson (2010) noted that pre-clinical data suggest improved complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity of ofatumumab compared with rituximab.  In early clinical trials, ofatumumab demonstrated single-agent activity against CLL and a number of histologies of B-cell NHL.  This antibody was recently approved by the Food and Drug Administration (FDA) for the treatment of CLL that is resistant to both fludarabine and alemtuzumab.  Additional study is ongoing with ofatumumab in combination with chemotherapy and biologic agents to further enhance its efficacy.

On October 26, 2009, Arzerra (ofatumumab) was approved under the Food and Drug Administration (FDA)'s accelerated approval process.  Arzerra was approved for patients with CLL whose cancer is no longer being controlled by other forms of chemotherapy, specifically fludarabine and alemtuzumab.  The labeling notes that the effectiveness of ofatumumab is based on demonstration of durable objective responses, and that no data demonstrate an improvement in disease-related symptoms or increased survival with ofatumumab.  The safety and effectiveness of Arzerra was examined in a single-arm, multi-center study in 154 patients with relapsed or refractory CLL (Study 1).  Arzerra was administered by IV infusion according to the following schedule: 300 mg (Week 0), 2,000 mg weekly for 7 infusions (weeks 1 through 7), and 2,000 mg every 4 weeks for 4 infusions (weeks 12 through 24).  Patients with CLL refractory to fludarabine and alemtuzumab (n = 59) comprised the efficacy population.  Drug refractoriness was defined as failure to achieve at least a PR to, or disease progression within 6 months of, the last dose of fludarabine or alemtuzumab.  The main efficacy outcome was durable objective tumor response rate.  Objective tumor responses were determined using the 1996 National Cancer Institute Working Group Guidelines for CLL.  In patients with CLL refractory to fludarabine and alemtuzumab, the median age was 64 years (range of 41 to 86 years), 75 % were male, and 95 % were White.  The median number of prior therapies was 5; 93 % received prior alkylating agents, 59 % received prior rituximab, and all received prior fludarabine and alemtuzumab.  Eighty-eight percent of patients received at least 8 infusions of Arzerra and 54 % received 12 infusions.  The investigator-determined overall response rate (ORR) in patients with CLL refractory to fludarabine and alemtuzumab was 42 % (99 % confidence interval [CI]: 26 to 60) with a median duration of response of 6.5 months (95 % CI: 5.8 to 8.3).  There were no complete responses.  Anti-tumor activity was also observed in additional patients in Study 1 and in a multi-center, open-label, dose-escalation study (Study 2) conducted in patients with relapsed or refractory CLL (SmithKline Beecham Corporation Product Insert for Arzerra, 2009).

Common side effects of Arzerra include cough, diarrhea, fatigue, fever, nausea, pneumonia, rash, shortness of breath, decreased normal white blood cell and red blood cell counts, as well as bronchitis and upper respiratory tract infections.  The most serious side effects of Arzerra are increased chance of infections, including progressive multifocal leukoencephalopathy (PML).  Patients at high-risk for hepatitis B should be screened before being treated with Arzerra.  Patients with evidence of inactive hepatitis should be monitored for re-activation of the infection during and after completing treatment (SmithKline Beecham Corporation Product Insert for Arzerra, 2009).

In April 2014, the FDA approved ofatumumab in combination with chlorambucil, for the treatment of previously untreated patients with CLL, for whom fludarabine-based therapy is considered inappropriate.  This approval was based on the results of a multi-center, randomized, open-label trial comparing ofatumumab in combination with chlorambucil to single agent chlorambucil.  The trial enrolled 447 patients for whom fludarabine-based therapy was considered to be inappropriate by the investigator for reasons that included advanced age or presence of co-morbidities.  In the overall trial population, the median age was 69 years (range of 35 to 92 years); 72 % of patients had 2 or more co-morbidities and 48 % of patients had a creatinine clearance of less than 70 ml/min.  Patients received ofatumumab as an intravenous infusion according to the following schedule: 300 mg administered on cycle 1 day 1, 1,000 mg administered on cycle 1 day 8 and 1,000 mg administered on day 1 of all subsequent 28-day cycles.  In both arms, chlorambucil was given at a dose of 10 mg/m2 orally on days 1 to 7 every 28 days.  Prior to each infusion of ofatumumab, patients received pre-medication with acetaminophen, an antihistamine, and a glucocorticoid. 

The primary end-point of the trial was progression free survival (PFS) as assessed by a blinded Independent Review Committee (IRC) using the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) update of the National Cancer Institute Working Group (NCI-WG) guidelines.  Median PFS was 22.4 months (95 % CI: 19.0 to 25.2 months) for patients receiving Arzerra in combination with chlorambucil compared to 13.1 months (95 % CI: 10.6 to 13.8 months) for patients receiving single-agent chlorambucil [hazard ratio (HR) 0.57 (95 % CI: 0.45 to  0.72), stratified log-rank p-value less than 0.001]. 

The most common adverse reactions (greater than or equal to 5 %) with ofatumumab in combination with chlorambucil (greater than or equal to 2 % more than in the control arm) were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia and upper abdominal pain.  Overall, 67 % of patients who received ofatumumab experienced 1 or more symptoms of infusion reaction; 10 % of patients experienced a grade 3 or greater infusion reaction. 

The results of this randomized trial were adequate to fulfill the postmarketing requirement for GlaxoSmithKline to verify the clinical benefit of ofatumumab and, therefore, the approval of ofatumumab was converted from accelerated approval to regular approval. 

Black Box Warnings

Hepatitis B Virus Reactivation

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with Arzerra. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with Arzerra. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with Arzerra. HBV reactivation has been reported for at least 12 months following completion of therapy.

In patients who develop reactivation of HBV while receiving ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of Arzerra in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming Arzerra in patients who develop HBV reactivation.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with Arzerra. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue Arzerra and initiate evaluation for PML including neurology consultation.

Arzerra (ofatumumab) should not be utilized in the following:

• Prior hypersensitivity (severe infusion reaction) to ofatumumab
• Women who are pregnant or lactating that have not been apprised of the potential hazard to the fetus
• Safety and efficacy have not been established in pediatric patients less than 18 years old
• Combination therapy with other biologicals such as Rituxan, Enbrel, Humira, Cimzia, Simponi, Amevive, Remicade, Orencia, Stelara, or Kineret
• Members that have experienced significant disease progression while on Arzerra (ofatumumab)

B-Cell Lymphomas

In a pilot, phase Ii clinical trial, Kiesewetter and colleagues (2018) evaluated the capacity and safety of ofatumumab (OFAB) to induce objective responses in patients with Helicobacter pylori eradication refractory or extra-gastric MALT lymphoma; OFAB was given at 4 weekly doses (1,000 mg) followed by 4 doses at 2-month intervals starting at week 8.  According to protocol, a total of 16 patients were recruited (median age of 69 years; range of 38 to 85); 5/16 (31 %) of patients had primary gastric MALT lymphoma while the remaining 69 % (11/16) presented with extra-gastric manifestations; 12/16 (75 %) had localized lymphoma and 4 patients disseminated disease.  The ORR to treatment with OFAB was 81 % (13/16), with the median time to best response being 5.5 months.  In detail, 50 % (8/16) achieved CR; 31 % (5/16), PR; and 19 % (3/16), stable disease (SD) as best response.  However, 1 patient with gastric lymphoma and CR at 2nd re-staging had a relapse at final assessment but ongoing CR during further follow-up.  Tolerability was excellent accept low-grade infusion reactions occurring in 86 % (14/16).  At a median follow-up time of 25 months only 1 patient has relapsed suggesting durable responses in the majority of patients.  The authors concluded that the findings of this pilot trial showed that OFAB is active and safe for the treatment of MALT lymphoma.

Waldenstrom Macroglobulinemia

Stedman and colleagues (2010) noted that Waldenstrom macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of the bone marrow (BM) with lympho-plasmacytic cells, as well as detection of an IgM monoclonal gammopathy in the serum.  Waldenstrom macroglobulinemia is an incurable disease, with an overall medial survival of only 5 to 6 years.  First-line therapy of WM has been based on single-agent or combination therapy with alkylator agents (e.g., chlorambucil or cyclophasphamide), nucleoside analogs (cladribine or fludarabine), and the monoclonal antibody rituximab.  Novel therapeutic agents that have demonstrated efficacy in WM include thalidomide, lenalidomide, bortezomib, everolimus, Atacicept, and perifosine.  The range of the ORR to these agents is between 25 to 80 %.  Ongoing and planned future clinical trials include those using protein-kinase C inhibitors such as enzastaurin, new proteasome inhibitors such as carfilzomib, histone deacetylase inhibitors such as panobinostat, humanized CD20 antibodies such as ofatumumab, and additional alkylating agents such as bendamustine.  These agents, when compared to traditional chemotherapeutic agents, may lead in the future to higher responses, longer remissions and better quality of life for patients with WM.

Other Indications

Acute Lymphoblastic Leukemia

Horvat and colleagues (2018) reviewed the pharmacology, safety, and efficacy of FDA-approved and promising immunotherapy agents used in the treatment of acute lymphoblastic leukemia (ALL).  These researchers performed a literature search of PubMed and Medline databases (1950 to July 2017) and of abstracts from the American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO).  Searches were performed utilizing the following key terms: rituximab, blinatumomab, inotuzumab, ofatumumab, obinutuzumab, Blincyto, Rituxan, Gazyva, Arzerra, CAR T-cell, and chimeric antigen receptor (CAR).  Studies of pharmacology, safety, and clinical efficacy of rituximab, ofatumumab, obinutuzumab, inotuzumab, blinatumomab, and CAR T-cells in the treatment of adult patients with ALL were identified.  Conventional chemotherapy has been the mainstay in the treatment of ALL, producing cure rates of approximately 90 % in pediatrics, but it remains sub-optimal in adult patients.  As such, more effective consolidative modalities and novel therapies for relapsed/refractory disease are needed for adult patients with ALL.  In recent years, anti-CD20 antibodies, blinatumomab, inotuzumab, and CD19-targeted CAR T-cells have drastically changed the treatment landscape of B-cell ALL.  The authors concluded that outcomes of patients with relapsed ALL are improving thanks to new therapies such as blinatumomab, inotuzumab, and CAR T-cells.  Moreover, they stated that although the efficacy of these therapies is impressive, they are not without toxicity, both physical and financial.  The optimal sequencing of these therapies still remains a question.

Furthermore, NCCN’s Drugs & Biologics Compendium (2019) does not list acute lymphoblastic leukemia as a recommended indication of ofatumumab.

In a single-arm, phase-II clinical trial, Jabbour and colleagues (2020) examined the activity and safety of ofatumumab in combination with chemotherapy in patients with Philadelphia chromosome (Ph)-negative CD20-positive B-cell ALL.  Patients with newly diagnosed, Ph-negative B-cell ALL or lymphoblastic lymphoma with CD20 expression of at least 1 % were eligible.  Patients were treated with up to 8 courses of the hyper-CVAD regimen (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) on courses 1, 3, 5, and 7 alternating with high-dose methotrexate and cytarabine on courses 2, 4, 6, and 8.  Ofatumumab was administered on days 1 and 11 of courses 1 and 3 and on days 1 and 8 of courses 2 and 4 for a total of 8 doses.  The 1st dose of ofatumumab was 300 mg intravenously and all subsequent doses were 2,000 mg intravenously.  Patients received 30 courses of maintenance therapy with 6-mercaptopurine, vincristine, methotrexate, and prednisone (POMP), with 4 intensification courses (high-dose methotrexate plus L-asparaginase and hyper-CVAD plus ofatumumab on courses 6 to 7 and 18 to 19).  The primary end-points were event-free survival (EFS), ORR, and OS.  All enrolled patients were included in the primary and safety analyses.  Between August 26, 2011 and May 18, 2017, 69 patients (67 patients had B-cell ALL and 2 had B-cell lymphoblastic lymphoma; median age of 41 years [inter-quartile range (IQR) 32-50]) were enrolled and treated, including 33 (48 %) aged between 18 and 39 years; 9 (27 %) of 33 patients had Ph-like ALL.  With a median follow-up of 44 months (26 to 53), 4-year EFS was 59 % (95 % CI: 48 to 73); 69 % (54 to 87) in adolescents and young adults aged 18 to 39 years; 4-year OS was 68 % (58 to 81); 74 % (60 to 91) in adolescents and young adults.  The ORR was 98 % (64 of 65 patients).  The most common non-hematological grade-3 or grade-4 AEs were infections (35 [54 %] of 65 patients during induction and 53 [78 %] of 68 patients during consolidation); 10 (14 %) of 69 patients died in complete remission from sepsis (2 [3 %]), cardiac arrest (1 [1 %]), therapy-related acute myeloid leukemia (AML; 2 [3 %]), and hematopoietic stem-cell transplantation (HSCT) complications (5 [7 %]).  None of these deaths was considered related to ofatumumab treatment by the study investigators.  The authors concluded that the combination of hyper-CVAD plus ofatumumab was safe and active in adults with Ph-negative CD20-positive B-cell ALL.  Moreover, these researchers stated that modifications of this regimen with the addition of novel monoclonal and bi-specific antibody constructs targeting CD19 and CD22 might further improve outcomes and allow reduction in the intensity and duration of chemotherapy.

Autoimmune Neutropenia / Idiopathic Thrombocytopenic Purpura

Castillo et al (2009) noted that lymphoproliferative and autoimmune disorders share monoclonal dysregulation and survival advantage of B-lymphocytes.  Thus, therapies directed towards eliminating B-cells will play an important role as CD20 is exclusively expressed in B-lymphocytes and its modulation by monoclonal antibodies such as rituximab has improved outcomes in lymphoproliferative and autoimmune disorders.  Ofatumumab is a new, fully human anti-CD20 antibody and has been shown to be effective and safe, but its role in these conditions is still unclear.  These investigators described the pre-clinical and clinical data available on ofatumumab for the treatment of lymphoproliferative and autoimmune disorders.  They carried out an extensive search of published articles and abstracts on pre-clinical and clinical studies with ofatumumab.  The authors concluded that ofatumumab is a 2nd-generation anti-CD20 antibody that has been demonstrated to be safe and efficacious in patients with lymphoproliferative and autoimmune disorders. Ofatumumab is fully human, attaches to a newly identified epitope and shows lower off-rates and improved complement-dependent cytotoxicity.  Initial data presented ofatumumab as an attractive agent with lower rates of infusion-related events than rituximab.  Phase-III clinical trials in patients with follicular lymphoma, chronic lymphocytic leukemia (CLL) and rheumatoid arthritis (RA) are ongoing, and phase-II clinical trials in patients with aggressive lymphoma and multiple sclerosis (MS) are also under development.

UpToDate reviews on “Immune thrombocytopenia (ITP) in adults: Initial treatment and prognosis” (George and Arnold, 201a), “Immune thrombocytopenia (ITP) in adults: Second-line and subsequent therapies” (George and Arnold, 2019b), “Immune thrombocytopenia (ITP) in children: Initial management” (Bussel, 2019a), and “Immune thrombocytopenia (ITP) in children: Management of chronic disease” (Bussel, 2019b) do not mention ofatumumab as a therapeutic option.

Furthermore, an UpToDate review on “Immune neutropenia” (Coates, 2019) does not mention ofatumumab as a therapeutic option.

Focal Segmental Glomerulosclerosis

Kienzl-Wagner and colleagues (2018) stated that primary focal segmental glomerulosclerosis (FSGS) recurs in up to 55 % after kidney transplantation.  These investigators reported the successful management of recurrent FSGS.  A 5-year old boy with primary FSGS received a deceased donor renal transplant.  Immediate and fulminant recurrence of FSGS caused anuric graft failure resistant to plasmapheresis and rituximab.  After exclusion of structural or immunological damage to the kidney by repeated biopsies, the allograft was retrieved from the first recipient on day 27 and transplanted into a 52-year old second recipient suffering from vascular nephropathy.  Immediately after re-transplantation, the allograft regained function with excellent graft function persistent now at 3 years post-transplant.  After 2 years on hemodialysis the boy was listed for kidney re-transplantation.  To prevent FSGS recurrence, a pre-treatment with ofatumumab was performed.  Nephrotic range proteinuria still occurred after the 2nd transplantation, which however responded to daily plasma exchange in combination with ofatumumab.  At 8 months after kidney re-transplantation graft function is good.  The authors concluded that the clinical course supported the hypothesis of a circulating permeability factor in the pathogenesis of FSGS; successful ofatumumab pre-treatment implicated a key role of B-cells.  These preliminary findings need to be validated by further investigation.

Furthermore, an UpToDate review on “Treatment of primary focal segmental glomerulosclerosis” (Cattran and Appel, 2018) does not mention ofatumumab as a therapeutic option.

Graft-Versus-Host Disease

In a phase I clinical trial, Pidala and colleagues (2015) examined the combination of standard (1 mg/kg/day prednisone) glucocorticoid therapy with ofatumumab for primary chronic graft-versus-host disease (GVHD) therapy. Patients aged 18 years or older with National Institutes of Health (NIH) Consensus moderate-to-severe chronic GVHD newly requiring 1 mg/kg/day prednisone were treated at 3 escalating dose levels (300 mg, 700 mg, and 1,000 mg) of intravenous ofatumumab on days 1 and 14 of initial glucocorticoid therapy. Dose-limiting toxicity (DLT) was defined by grade 4 infusion reactions, related grade 4 constitutional symptoms, related grade greater than or equal to 3 organ toxicities, or grade 4 neutropenia lasting more than 14 days. A total of 12 patients (median age of 54 years; range of 25 to 72) were treated (dose level 1: n = 3; level 2: n = 3; and level 3: n = 6). At enrollment, overall chronic GVHD was moderate (n = 7) or severe (n = 5), with diverse organ involvement (skin: n = 8; mouth: n = 8; eye: n = 8; lung: n = 4; gastro-intestinal: n = 3; liver: n = 5; genital: n = 2; joint/fascia: n = 5). Infusion of ofatumumab was well-tolerated, and no DLT was observed. From the total number of AEs (n = 29), possibly related AEs (n = 4) included grade 1 fatigue, grade 1 transaminitis, and 2 infusion reactions (grades 2 and 3). Infectious complications were expected, and there were no cases of hepatitis B reactivation or progressive multifocal leukoencephalopathy (PML). The authors concluded that ofatumumab in combination with prednisone is safe and a phase II examination of efficacy is ongoing.

Hodgkin Lymphoma

In a phase II clinical trial, Martínez and colleagues (2016) examined the activity of OFAB in combination with etoposide, steroids, cytarabine and cisplatin (O-ESHAP) in 62 patients with recurrent/refractory (R/R) classical Hodgkin lymphoma (HL).  Treatment consisted of ESHAP plus OFAB 1,000-mg on days 1 and 8 of the 1st cycle and day 1 of the 2nd and 3rd cycles.  O-ESHAP was well-tolerated with only 3 % of patients requiring treatment discontinuation because of AEs; ORR was 73 % (44 % complete metabolic response).  In multi-variate analysis, early relapse (p < 0·001), bulky disease (p < 0·001) and B symptoms (p < 0·001) were the most important prognostic factors for response.  No failures of stem cell mobilization were observed.  The authors stated that the high response rate, particularly the complete metabolic response rate, the low toxicity profile, and the high mobilizing potential of the O-ESHAP regimen suggested that patients with R/R HL may benefit from this salvage regimen.  However, with the encouraging results observed with other new therapeutic agents in HL, the O-ESHAP regimen could be restricted to patients failing these agents or to those with R/R nodular lymphocyte-predominant HL.

Lupus Nephritis

In a single-case report, Haarhaus and colleagues (2016) described, for the first time, treatment with OFAB in 4 patients with lupus nephritis (LN).  The treatment was well-tolerated in 3 of the patients, and a reduction of proteinuria was seen in all cases.  This emphasized the importance of alternative B-cell-depleting therapies in LN patients with an initial good response to RTX, but who developed AEs.  Ofatumumab reduced albuminuria in all 4 cases.  The authors suggested that OFAB be considered as an alternative treatment for LN in patients who, after initial good response, developed reactions to RTX.  They stated that RCTs are needed to establish the effectiveness of OFAB and to determine the optimal treatment regimen in LN.

Lymphomas - Other

Gupta and Jewell (2012) noted that ofatumumab is the first human anti-CD20 monoclonal antibody to be approved for patients in the United States and the European Union.  Ofatumumab received accelerated approval from the U.S. FDA in October 2009 and was granted a conditional marketing authorization by the European Medicines Agency in April 2010 for the treatment of patients with CLL refractory to fludarabine and alemtuzumab, based on interim results of a pivotal phase 2 trial.  Preliminary positive results for ofatumumab in combination with chemotherapy in patients with CLL are currently being confirmed in larger randomized trials in both the front-line setting as well as the relapsed/refractory setting.  Ofatumumab has also shown potential in treating B cell non-Hodgkin's lymphoma, such as follicular lymphoma, diffuse large B cell lymphoma, and Waldenström's macroglobulinemia.  The authors stated that additional trials are ongoing to confirm activity of ofatumumab as monotherapy and in combination with chemotherapy in patients with follicular lymphoma or diffuse large B cell lymphoma.

Matasar and colleagues (2013) stated that standard treatment of transplant-eligible patients with relapsed diffuse large B-cell lymphoma (DLBCL) consists of rituximab and platinum-based chemotherapy, either ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, cytarabine, and cisplatin (DHAP), with autologous transplant consolidation for those with chemosensitive disease.  Nonetheless, outcomes are suboptimal for patients failing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).  These researchers performed a multi-center phase II trial investigating the safety and effectiveness of ofatumumab combined with ICE or DHAP second-line therapy in patients with relapsed or refractory DLBCL, grade 3b follicular lymphoma, or transformed follicular lymphoma.  A total of 61 patients were treated with either ofatumumab-ICE (n = 35) or ofatumumab-DHAP (n = 26).  The ORR was 61 %, and the CR rate was 37 %.  In patients with 2 or 3 adverse risk factors according to the second-line, age-adjusted, international prognostic index, the ORR was 59 % and CR 31 %, and in patients with early-relapsing or primary refractory disease, the ORR was 55 % and CR 30 %.  Toxicity was largely hematologic, and stem cell mobilization was successful in 43 of 45 patients.  The authors concluded that substitution of ofatumumab for rituximab in standard second-line regimens following failure of R-CHOP is a promising approach.

In a phase I/II clinical study, Hagenbeek et al (2008) evaluated the safety and effectiveness of ofatumumab in relapsed or refractory follicular NHL (FL) grade 1 or 2.  Four dose groups of 10 patients received 4 weekly infusions of 300, 500, 700, or 1,000 mg.  Patients had a median of 2 prior FL therapies and 13 % had elevated lactate dehydrogenase.  No safety concerns or maximum tolerated dose (MTD) was identified.  A total of 274 adverse events were reported; 190 were judged related to ofatumumab, most occurring on the first infusion day with Common Terminology Criteria grade 1 or 2.  Eight related events were grade 3.  Treatment caused immediate and profound B-cell depletion, and 65 % of patients reverted to negative BCL2 status.  Clinical response rates ranged from 20 % to 63 %.  Median time to progression for all patients/responders was 8.8/32.6 months, and median duration of response was 29.9 months at a median/maximum follow-up of 9.2/38.6 months.  The authors noted that ofatumumab is currently being evaluated in patients with rituximab-refractory FL.

Multiple Sclerosis

The clinical success of B-cell depletion using the anti-CD20 antibody rituximab has sparked a new era in the therapy of rheumatic diseases.  In this regard, ofatumumab has also been studied in the treatment of rheumatoid arthritis (RA) as well as other autoimmune diseases (e.g., Crohn's disease, multiple sclerosis, vasculitis, and Wegener's granulomatosis).  Dorner and Burmester (2008) reviewed therapeutic approaches of direct and indirect B-cell targeting in autoimmune diseases and their impact on protective immunity.  They noted that beyond recent clinical experiences with rituximab as B-cell-depleting agent, other biologicals targeting CD20, such as ocrelizumab, ofatumumab, hA20, and TRU-015 mainly deplete B cells and are under clinical investigation in different entities.  Moreover, anti-CD22 targeting as another approach that has been studied in clinical trials showed a modest depletion, but inhibition of B-cell activation.  More indirect innovative B-cell-affecting therapies comprise blockade of cytokines, such as B-cell-activating factor, and their receptors as well as blockade of co-stimulation.  Although decreases of immunoglobulin levels were seen, so far no major increases in infections were reported.  The authors concluded that the value of certain B-cell-depletion therapies as well as other therapies modulating B-cell functions needs to be further delineated, especially in the therapeutic regimen of RA, specific collagen vascular diseases and vasculitis.  They stated that long-term observations of protective immunity are also needed to further evaluate the rate of infections.  Furthermore, Castillo et al (2009) stated that phase II clinical trials of ofatumumab for patients with aggressive lymphoma and multiple sclerosis are also under development.

Nicholas et al (2012) stated that the therapeutic landscape for multiple sclerosis (MS) is rapidly changing.  Currently, there are 8 FDA-approved disease modifying therapies for MS including: IFN-β-1a (Avonex, Rebif), IFN-β-1b (Betaseron, Extavia), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri), and fingolimod (Gilenya).  These investigators highlighted the experience to-date and key clinical trials of the newest FDA-approved agents, natalizumab and fingolimod.  They also reviewed available safety and effectiveness data on several promising therapies under active investigation including four monoclonal antibody therapies: alemtuzumab, daclizumab, ocrelizumab and ofatumumab and 3 agents: BG12, laquinimod, and teriflunomide.

In a randomized, double-blind, placebo-controlled, phase II clinical trial, Sorensen et al (2014) examined the safety and effectiveness of ofatumumab in relapsing-remitting multiple sclerosis (RRMS). Patients received 2 ofatumumab infusions (100 mg, 300 mg, or 700 mg) or placebo 2 weeks apart. At week 24, patients received alternate treatment; safety and efficacy were assessed. A total of 38 patients were randomized (ofatumumab/placebo, n = 26; placebo/ofatumumab, n = 12) and analyzed; 36 completed the study. Two patients in the 300-mg group withdrew from the study because of adverse events. No unexpected safety signals emerged. Infusion-related reactions were common on the first infusion day but not observed on the second infusion day. None of the patients developed human anti-human antibodies. Ofatumumab was associated with profound selective reduction of B cells as measured by CD19(+) expression. New brain MRI lesion activity was suppressed (greater than 99 %) in the first 24 weeks after ofatumumab administration (all doses), with statistically significant reductions (p < 0.001) favoring ofatumumab found in new T1 gadolinium-enhancing lesions, total enhancing T1 lesions, and new and/or enlarging T2 lesions. The authors concluded that ofatumumab (up to 700 mg) given 2 weeks apart was not associated with any unexpected safety concerns and was well-tolerated in patients with RRMS; MRI data suggested a clinically meaningful effect of ofatumumab for all doses studied. The authors concluded that these findings warrant further exploration of ofatumumab in RRMS.

In 2 double-blind, double-dummy, phase-III clinical trials, Hauser and colleagues (2020) randomly assigned patients with relapsing MS to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months.  The primary end-point was the annualized relapse rate.  Secondary end-points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.  A total of 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years.  The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95 % CI: -0.16 to -0.06; p < 0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95 % CI: -0.20 to -0.09; p < 0.001).  In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9 % with ofatumumab and 15.0 % with teriflunomide (HR, 0.66; p = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1 % and 12.0 %, respectively (HR, 0.68; p = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0 % and 8.1 % (HR, 1.35; p = 0.09).  The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end-point.  Injection-related reactions occurred in 20.2 % in the ofatumumab group and in 15.0 % in the teriflunomide group (placebo injections).  Serious infections occurred in 2.5 % and 1.8 % of the patients in the respective groups.  The authors concluded that ofatumumab was associated with lower annualized relapse rates than teriflunomide and showed benefit with respect to most secondary clinical and MRI end-points but not confirmed disability improvement.  Ofatumumab was associated with a higher frequency of injection-related systemic reactions, predominantly with the 1st injection, than was placebo injection.  Moreover, these researchers stated that larger and longer trials are needed to determine the long-term effect and risks of ofatumumab as compared with other disease-modifying treatments, including other anti-CD20 monoclonal antibodies.

Nephropathy / Nephritic-Nephrotic Syndrome

Lundberg and colleagues (2017) described clinical outcomes after 17 to 22 months in 4 adult patients with biopsy-confirmed IgA vasculitis with nephritis (IgAVN) or immunoglobulin A (IgA) nephropathy (IgAN) treated with RTX or OFAB as well as CS soon after diagnosis.  All presented with nephritic-nephrotic syndrome and 1 had crescentic IgAN.  Re-biopsy was performed in 2 cases; RTX and OFAB were well-tolerated.  Albuminuria was less than 250 mg/day in 3 patients at last evaluation and 2 regained normal renal function.  In all cases, renal function improved after therapy.  In 1 patient with severe IgA vasculitis, re-biopsy showed disappearance of sub-endothelial but not mesangial immune complexes.  In the case with crescentic IgAN, re-biopsy after 9 months showed no active necrotic lesions.  The authors concluded that the findings of this case series demonstrated that B cell-depleting therapy with RTX or OFAB may be an effective therapeutic option in patients with IgAN or IgAVN and clinical as well as histological signs of highly active inflammation.  Repeated treatment may be necessary and further follow-up is needed to evaluate the long-term clinical outcome and safety of this therapeutic approach.  Moreover, they stated that the rarity of rapid progressive glomerulonephritis in IgAN and IgAVN needs to be addressed in multi-center clinical trials and B cell-depleting therapy without any CS should be further evaluated; results are awaited from an open-label, randomized trial on RTX versus supportive care in IgAN that has recently been completed.

Nephrotic Syndrome

Wang and associates (2017) reported their experience in administering OFAB to 5 pediatric patients with idiopathic nephrotic syndrome (INS).  Between March 2015 and November 2016, 5 patients were treated with OFAB; 1 patient had post-transplant recurrent focal segmental glomerulosclerosis (FSGS) that had been resistant to plasmapheresis and numerous immunosuppressive agents; 4 patients had nephrotic syndrome in their native kidneys, 1 with initial steroid-resistant disease and the others with subsequent development of steroid resistance; 2 of the patients were treated with a desensitization protocol after experiencing hypersensitivity reactions to OFAB.  One patient did not complete OFAB treatment due to infusion reactions.  Of the 4 remaining patients, 3 achieved CR after treatment, and 1 achieved PR.  One of the patients achieving CR represented the 1st reported case of successful treatment of post-transplant recurrent FSGS using OFAB; 2 patients who received OFAB with the desensitization protocol were able to complete their treatments after initially experiencing hypersensitivity reactions.  The authors concluded that OFAB may be an effective treatment for refractory childhood nephrotic syndrome and post-transplant recurrent FSGS; a desensitization protocol may be helpful to address hypersensitivity reactions.

Ravani and colleagues (2107) described the study protocol of a RCT comparing OFAB to RTX in children with calcineurin inhibitor (CNI)-dependent and steroid-dependent INS (SD-INS).  This open-label, 2-parallel-arm, controlled, phase II clinical trial will enroll children with SD-INS maintained in remission with oral steroids and CNI.  Children will be randomized to either OFAB or RTX infusion.  After infusion of either antibody, steroids will be maintained for 30 days and then tapered off by 0.3 mg/kg/week until complete withdrawal; 1 week after complete steroid withdrawal, CNI will be decreased by 50 % and withdrawn within 2 additional weeks.  These researchers will enroll a total of 140 children to detect as significant at the 2-sided p value of 0.01 with a power of greater than 0.8, a reduction in the risk of 1-year relapse (primary end-point) of at least 0.3 (i.e., from 0.65 to 0.35; (risk ratio 0.54)) in the OFAB-arm when compared with the RTX-arm.  These investigators will compare the amount of steroids needed to maintain CR at 6 and 24 months, relapse-free period, relapse rate per year as secondary end-points.  Circulating cell populations will be studied as biomarkers or predictors of the anti-CD20 response.

Opsoclonus-Myoclonus Syndrome

In a case study, Pranzatelli and associates (2012) used ofatumumab in the treatment of a rituximab-allergic child with severe, chronic-relapsing, opsoclonus-myoclonus syndrome (OMS), characterized by persistent cerebrospinal fluid (CSF) B-cell expansion and T-cell dysregulation.  The patient had relapsed despite chemotherapy, plasma exchange with immunoadsorption, and resection of ganglio-neuroblastoma, detected 3 years after OMS onset.  The 4 ofatumumab infusions (1,195 mg/m(2) total dose) were well- tolerated, and CSF B-cell expansion was eliminated.  No further relapses have occurred in 3 years, but he remains on low-dose adrenocorticotropic hormone with neuropsychiatric residuals of OMS.  The effectiveness of ofatumumab in the treatment of OMS needs to be examined in well-designed studies.

Pemphigus Vulgaris

Rapp and colleagues (2018) noted that rituximab is a chimeric anti-CD20 monoclonal antibody that is very effective in treating patients with pemphigus vulgaris.  Though infrequent, the development of human anti-chimeric antibodies in patients receiving rituximab results in loss of efficacy.  Ofatumumab is a 2nd-generation fully-human anti-CD20 monoclonal antibody currently used to treat CLL.  These investigators reported a case of a patient with pemphigus vulgaris successfully treated with ofatumumab after developing human anti-chimeric antibodies to rituximab.  The findings from this single-case study need to be validated by well-designed studies.

Rheumatoid Arthritis

In a phase I/II randomized, double-blind, placebo-controlled, clinical trial, Ostergaard and colleagues (2010) examined the safety and effectiveness of ofatumumab in patients with active RA whose disease did not respond to greater than or equal to 1 disease-modifying anti-rheumatic drug.  This study investigated the safety and effectiveness of 3 doses of ofatumumab.  In part A (phase I), 39 patients received 2 intravenous (i.v.) infusions of ofatumumab (300 mg, 700 mg, or 1,000 mg) or placebo in a 4:1 ratio 2 weeks apart, using a specified pre-medication and infusion regimen.  In part B (phase II), 225 patients received study treatment as per phase I in a 1:1:1:1 ratio.  Safety was assessed by adverse events (AEs) and laboratory parameters.  Effectiveness was assessed by the American College of Rheumatology 20 % criteria for improvement (ACR20), the Disease Activity Score in 28 joints, and the European League Against Rheumatism (EULAR) response criteria; B cell pharmacodynamics were also investigated.  Adverse events were predominantly reported at the first infusion and were mostly mild-to-moderate in intensity.  Rapid and sustained peripheral B cell depletion was observed in all dose groups.  In phase II, patients in all ofatumumab dose groups had significantly higher ACR20 response rates (40 %, 49 %, and 44 % for the 300 mg, 700 mg, and 1,000 mg doses, respectively) than did patients receiving placebo (11 %) at week 24 (p < 0.001).  Overall, 70 % of patients receiving ofatumumab had a moderate or good response according to the EULAR criteria at week 24.  The authors concluded that these findings indicate that ofatumumab, administered as 2 i.v. infusions of doses up to 1,000 mg, is clinically effective in patients with active RA.  These findings need to be validated by phase III studies with larger number of subjects and longer follow-up.

In a review on “Current standards and future treatments of rheumatoid arthritis”, Onysko and Burch (2012) listed ofatumumab as an emerging therapy for RA.

Richter Syndrome

Eyre and colleagues (2016) stated that Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median OS of 8 to 10 months.  These researchers carried out a phase II clinical trial of standard CHOP-21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 days) with OFAB induction (Cycle 1: 300-mg day 1, 1,000-mg day 8, 1,000-mg day 15; Cycles 2 to 6: 1,000-mg day 1) (CHOP-O) followed by 12 months OFAB maintenance (1,000-mg given 8-weekly for up to 6 cycles).  A total of 43 patients were recruited of whom 37 were evaluable; 73 % were aged greater than 60 years.  Over 50 % of the patients received a fludarabine and cyclophosphamide-based regimen as prior CLL treatment.  The ORR was 46 % (CR 27 %, PR 19 %) at 6 cycles.  The median PFS was 6.2 months (95 % CI: 4.9 to 14.0 months) and median OS was 11.4 months (95 % CI: 6.4 to 25.6 months).  Treatment-naïve and TP53-intact patients had improved outcomes; 15 episodes of neutropenic fever and 46 non-neutropenic infections were observed.  There were no treatment-related deaths; 7 patients received platinum-containing salvage at progression, with only 1 patient obtaining an adequate response to proceed to allogeneic transplantation.  The authors concluded that CHOP-O with OFAB maintenance provided minimal benefit beyond CHOP plus RTX.  They stated that standard immunochemotherapy for RS remains wholly inadequate for unselected RS; multi-national trials incorporating novel agents are urgently needed.

Systemic Lupus Erythematosis

Robak and Robak (2009) stated that systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell hyperactivity and defective T-cell function, with production of high titer autoantibodies.  In recent years, conceptual advances and the introduction of new therapies are yielding improvements in the management of this disease.  Clinical studies have been undertaken with selected monoclonal antibodies (mAbs) in the treatment of SLE.  The important role of B cells in the pathogenesis of autoimmune disorders has provided a strong rationale to target B cells in SLE.  Selective therapeutic depletion of B-cells became possible with the availability of the anti-CD20 antibody rituximab and anti-CD22 antibody epratuzumab.  Several clinical studies confirm high activity of rituximab in SLE patients especially with lupus nephritis and neuropsychiatric involvement.  Recently, several new mAbs reacting with CD20 have been developed.  New mAbs directed against CD20 include fully human mAb ofatumumab, IMMU-106 which has a greater than 90 % humanized framework and GA-101, a novel third-generation fully humanized and optimized mAb.  These agents are highly cytotoxic against B-cell lymphoid cells.  Pro-inflammatory cytokines such as tumor necrosis factor-alpha and iterleukin-6 play an important role in propagating the inflammatory process responsible for tissue damage. Blocking of these cytokines by mAbs can be also a successful therapy for patients with SLE.

Vasculitis

In a single-center, case-series study, McAdoo and colleagues (2016) studied the use of OFAB in the treatment of ANCA-associated vasculitis (AAV).  This study included 8 patients who received OFAB in conjunction with low-dose cyclophosphamide (CYC) and oral steroids, in the treatment of AAV -- 7 for remission induction in active disease (3 relapsing; 4 with new disease) and 1 for remission maintenance.  B-cell depletion was achieved in all patients by 1 month, and was sustained for at least 6 months.  All patients with active disease achieved clinical remission (Birmingham Vasculitis Activity Score [BVAS] of zero, or BVAS less than or equal to 5 if all scores due to persistent urinary abnormalities in the presence of stable or improving renal function) by 3 months.  This was associated with a rapid fall in ANCA titers, reduced inflammatory responses and improvements in renal function.  At 12 months, 3 patients had re-populated B-cells associated with the recurrence of circulating ANCAs, although no patients experienced major clinical relapse in the first 24 months.  No unexpected AEs  were observed.  The authors concluded that treatment with OFAB resulted in similar serological and clinical responses to those seen in previous cohorts treated at the authors’ center with a comparable corticosteroid (CS), CYC and rituximab (RTX)-based regimen.  They stated that OFAB should be considered an alternative B-cell-depleting agent in patients who are intolerant of, or unresponsive to RTX.  Moreover, they stated that larger studies, including randomized controlled trials (RCTs), are needed to more precisely define the role of this and other emerging anti-B cell therapies in AAV.  Pending these studies, this series provided a potential dosing regimen and preliminary evidence that OFAB may be a useful alternative agent in the treatment of AAV.

Appendix

Table: Brands of Targeted Immune Modulators and FDA-approved Indications:

Brand Name	Generic Name	FDA Labeled Indications
Actemra	tocilizumab	Giant cell arteritis Juvenile idiopathic arthritis Rheumatoid arthritis Systemic juvenile idiopathic arthritis Cytokine release syndrome (CRS)
Cimzia	certolizumab	Ankylosing spondylitis Crohn's disease Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Cosentyx	secukinumab	Ankylosing spondylitis Plaque psoriasis Psoriatic arthritis
Enbrel	etanercept	Ankylosing spondylitis Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthrits Rheumatoid arthritis
Entyvio	vedolizumab	Crohn's disease Ulcerative colitis
Humira	adalimumab	Ankylosing spondylitis Crohn's disease Hidradenitis suppurativa Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis Uveitis
Ilaris	canakinumab	Periodic fever syndromes   Systemic juvenile idiopathic arthritis
Ilumya	tildrakizumab-asmn	Plaque psoriasis
Inflectra	infliximab	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Kevzara	sarilumab	Rheumatoid arthritis
Kineret	anakinra	Cryopyrin-associated periodic syndromes Rheumatoid arthritis
Olumiant	baricitinib	Rheumatoid arthritis
Orencia	abatacept	Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Otezla	apremilast	Plaque psoriasis Psoriatic arthritis
Remicade	infliximab	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Rituxan	rituximab	Granulomatosis with polyangiitis Microscopic polyangiitis Pemphigus vulgaris Rheumatoid arthritis
Siliq	brodalumab	Plaque psoriasis
Simponi	golimumab	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Simponi Aria	golimumab intravenous	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis
Stelara	ustekinumab	Crohn's disease Plaque psoriasis Psoriatic arthritis
Taltz	ixekinumab	Plaque psoriasis Psoriatic arthritis
Tremfya	guselkumab	Plaque psoriasis
Tysabri	natalizumab	Crohn's disease Multiple sclerosis
Xeljanz	tofacitinib	Rheumatoid arthritis Psoriatic arthritis Ulcerative Colitis
Xeljanz XR	tofacitinib, extended release	Rheumatoid arthritis Psoriatic arthritis Ulcerative colitis

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96379	Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion
96413	Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug
96415	Chemotherapy administration, intravenous infusion technique; each additional hour (List separately in addition to code for primary procedure)
HCPCS codes covered if selection criteria are met:
J9302	Injection, ofatumumab, 10 mg [Arzerra]
Other HCPCS codes related to the CPB:
J3245	Injection, tildrakizumab, 1 mg
ICD-10 codes covered if selection criteria are met:
C82.00 - C82.49 C82.60 - C82.99	Follicular lymphoma
C83.10 - C83.19	Mantle cell lymphoma
C83.30 - C83.39	Diffuse large B-cell lymphoma
C83.70 - C83.89	Burkitt lymphoma
C85.10 - C85.29	B-cell lymphomas
C88.4	Marginal zone lymphoma
C88.0	Waldenstrom macroglobulinemia
C91.10	Chronic lymphocytic leukemia of b-cell type not having achieved remission [refractory and previously untreated persons whom fludarabine-based therapy is considered inappropriate] [chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)]
C91.12	Chronic lymphocytic leukemia of b-cell type in relapse [chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)]
D47.Z1	Post-transplant lymphoproliferative disorders
D47.Z2	Castleman’s disease
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C81.0 - C81.99	Hodgkin lymphoma
C91.00 - C91.02	Acute lymphoblastic leukemia [ALL]
D69.3	Immune thrombocytopenic purpura
D70.8	Other neutropenia [autoimmune neutropenia]
D80.0 - D84.9 D89.810 - D89.9	Disorders involving the immune mechanism
E05.00 - E05.01	Thyrotoxicosis with diffuse goiter [Graves' disease]
E06.3	Autoimmune thyroditis [Hashimoto's disease]
E27.1 - E27.49 E89.6	Other disorders of adrenal gland [Addison's disease]
G35	Multiple sclerosis
G61.0	Guillain-Barre syndrome
G70.00 - G70.01 G73.3	Myasthenia gravis
H55.89	Other irregular eye movements [paraneoplastic opsoclonus-myoclonus]
I77.6	Arteritis, unspecified [vasculitis]
K50.00 - K50.919	Regional enteritis [Crohn's disease]
K58.0 - K58.9	Irritable bowel syndrome
K75.4	Autoimmune hepatitis
K90.0	Celiac disease
L10.0	Pemphigus vulgaris
L40.0 - L40.9	Psoriasis
M05.00 - M05.09 M05.20 - M06.39 M06.80 - M06.9 M08.00 - M08.09 M08.20 - M08.99	Rheumatoid arthritis
M31.0	Hypersensitivity angiitis [Goodpasture's syndrome]
M31.30 - M31.31	Wegener's granulomatosis
M32.0 - M32.9	Systemic lupus erythematosus
M34.0 - M34.9	Systemic sclerosis [scleroderma]
M35.00 - M35.09	Sicca syndrome [Sjögren's disease]
N02.0 - N02.9	Recurrent and persistent hematuria
N04.0 - N04.9	Nephrotic syndrome
N05.0 - N05.9	Unspecified nephrotic syndrome
N07.0 - N07.9	Hereditary nephropathy, not elsewhere classified
N13.8	Other obstructive and reflux uropathy
N14.0 - N14.4	Drug-and heavy-metal-induced tubule-interstitial and tubular conditions
N15.0	Balkan nephropathy
N17.2	Acute kidney failure with medullary necrosis
N25.81 - N25.89	Other disorders resulting from impaired renal tubular function
N26.9	Renal sclerosis, unspecified

The above policy is based on the following references: