Obinutuzumab (Gazyva)

Number: 0877

Policy

Aetna considers obinutuzumab medically necessary for the followiing indications in persons without active hepatitis B infection:

B-Cell Lymphomas

  • Treatment of follicular lymphoma when any of the following criteria are met:
     
    • In combination with:
       
      • CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or 
      • CVP (cyclophosphamide, vincristine, and prednisone) regimen; or
      • bendamustine; or

    • As maintenance therapy
       
  • Gastric MALT lymphoma, nodal marginal zone lymphoma, non-gastric MALT lymphoma and splenic marginal zone lymphoma when any of the following criteria are met:
     
    • Second-line or subsequent therapy in combination with bendamustine; or
    • As maintenance therapy when the member has been previously treated with obinutuzumab and bendamustine regimen; or 

  • B-cell Lymphomas (including hiistologic Transformation of Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, Diffuse Large B-Cell Lymphoma, High-Grade B-Cell Lymphomas, Burkitt Lymphoma, AIDS-Related B-Cell Lymphomas, Post-Transplant Lymphoproliferative Disorders, and Castleman’s Disease) as a substitute for rituximab in members experiencing rare complications (e.g., mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis) since re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

  • Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)

Gazyva (obinutuzumab) therapy is considered medically necessary when members meet the initial criteria and have not experienced disease progression or unacceptable toxicity while on obinutuzumab.

Aetna considers obinutuzumab experimental and investigational for all other indications including the following (not an all-inclusive list):

  • Acute lymphoblastic leukemia
  • Anti-MAG demyelinating neuropathy
  • Autoimmune bullous diseases (e.g., pemphigus vulgaris)
  • B-cell prolymphocytic leukemia
  • Lymphoma of the cervix
  • Rheumatoid arthritis
  • Systemic lupus erythematosus.

Dosing Recommendations

The recommended dose and schedule for the regimen are as follows:

Obinutuzumab: 1,000 mg by intravenous infusion on days 1, 8 and 15 of cycle 1; on day 1 of cycles 2 to 6 (28-day cycles); and then every 2 months for 2 years.

Bendamustine: 90 mg/m2 by intravenous infusion on days 1 and 2 of cycles 1 to 6.

Source: AbbVie Inc., May 2019.

Background

Gazyva (obinutuzumab) is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre B‐ and mature B‐lymphocytes. Upon binding to CD20, obinutuzumab mediates B‐cell lysis through
  1. engagement of immune effector cells,
  2. by directly activating intracellular death signaling pathways and/or
  3. activation of the complement cascade.
The immune effector cell mechanisms include antibody‐dependent cellular cytotoxicity and antibody‐dependent cellular phagocytosis. Obinutuzumab in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).

Chronic lymphocytic leukemia (CLL) represents the most prevalent adult leukemia and the introduction of therapeutic antibodies has increased the number of available treatments.  For both previously untreated symptomatic CLL and as salvage therapy, rituximab, a CD20 antibody, is currently widely used in combination-based strategies.  Recent data suggest that the addition of rituximab to fludarabine with or without cyclophosphamide prolongs survival in younger patients with CLL.  Other improved CD20 antibodies with promising clinical activity, include ofatumumab and obinutuzumab (GA-101).  Alemtuzumab, a CD52 antibody, likewise has demonstrated benefit in both symptomatic, previously untreated CLL and in patients with relapsed disease.  Also, recent efforts to combine currently applied therapeutic antibodies with other biologic and targeted therapies with efficacy in CLL offers the potential to move toward alternative non-chemotherapy-based treatment approaches (Jaglowski et al, 2010).

Laprevotte et al (2013) reported that rituximab combined with chemotherapy is a standard treatment for CLL.  They investigated whether endogenous IL-8 affects rituximab or obinutuzumab (GA-101) B-leukemic depletion mediated by natural killers. Rituximab, and more significantly obinutuzumab, were effective in B-cell depletion and natural killer activation using whole peripheral blood lymphocytes from untreated CLL patients.

Obinutuzumab was approved on November 1, 2013 by the Food and Drug Administration (FDA) for use in combination with chlorambucil for previously untreated CLL (NCI, 2013).  Obinutuzumab is a CD20-cytolytic antibody.  The FDA labeling produced by Genentech (2013) lists a boxed warning stating that “hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA.  Screen all patients for HBV infection before treatment initiation.  Monitor HBV positive patients during and after treatment with GAZYVA.  Discontinue GAZYVA and concomitant medications in the event of HBV reactivation... Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA”.

Obinutuzumab is available as Gazyva in 1000mg/40mL single dose vials. Dosing and administration of obinutuzumab includes premedication with glucocorticoid, acetaminophen and anti-histamine.  Obinutuzumab is to be diluted and administered as intravenous infusion and is not to be administered as an intravenous push or bolus.  The recommended dose for 6 cycles (28 day cycles) for CLL/SLL is as follows: 100 mg on day 1 Cycle 1; 900 mg on day 2 Cycle 1; 1,000 mg on day 8 and 15 of Cycle 1; and 1,000 mg on day 1 of Cycles 2 through 6 (Genentech, 2013). Currently available data limits the use of Gazyva (obinutuzumab) to six cycles.

An FDA news release stated that "Gazyva’s approval for CLL is based on a study of 356 participants in a randomized open-label multi-center trial comparing Gazyva in combination with chlorambucil to chlorambucil alone in participants with previously untreated CLL. Participants receiving Gazyva in combination with chlorambucil demonstrated a significant improvement in progression free survival: an average of 23 months compared with 11.1 months with chlorambucil alone" (FDA, 2013).

Gazyva has the following black box boxed warnings:

Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death.

Progressive Multifocal Leukoencephalopathy (PML) resulting in death.

On May 15, 2019, the Food and Drug Administration approved venetoclax (Venclexta) for adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Approval was based on CLL14 (NCT02242942), a randomized (1:1), multicenter, open label, actively controlled phase 3 trial of venetoclax in combination with obinutuzumab (Gazyva) (VEN+G) versus obinutuzumab in combination with chlorambucil (GClb) in 432 patients with previously untreated CLL with coexisting medical conditions (total Cumulative Illness Rating Scale [CIRS] score > 6 or CLcr < 70 mL/min). The trial required hepatic transaminases and total bilirubin ≤2 times upper limit of normal and excluded patients with Richter’s transformation or any individual organ/system impairment score of 4 by CIRS except eye, ear, nose, and throat organ system. All patients received obinutuzumab at 1000 mg on Day 1 (the first dose could be split as 100 mg and 900 mg on Days 1 and 2), and on Days 8 and 15 of Cycle 1, and on Day 1 of each subsequent cycle, for a total of 6 cycles. Patients in the VEN+G arm began the 5-week venetoclax ramp-up schedule on Day 22 of Cycle 1, and received venetoclax 400 mg once daily from Cycle 3 Day 1 until the last day of Cycle 12. Patients randomized to the GClb arm received 0.5 mg/kg oral chlorambucil on Day 1 and Day 15 of Cycles 1 to 12. Each cycle was 28 days. A total of 432 patients were randomized, 216 to each study arm. Baseline demographic and disease characteristics were similar between the study arms. The median age was 72 years (range: 41 to 89 years), 89% were white, 67% were male; 36% and 43% were Binet stage B and C, respectively, and 88% had ECOG performance status <2. The median CIRS score was 8.0 (range: 0 to 28) and 58% of patients had CLcr <70 mL/min. A 17p deletion was detected in 8% of patients, TP53 mutations in 7%, 11q deletion in 19%, and unmutated IgVH in 57%. The major efficacy outcome was progression-free survival (PFS) assessed by an independent review committee. The investigators concluded that this trial demonstrated a statistically significant improvement in PFS for patients who received VEN+G compared with those who received GClb (HR 0.33; 95% CI: 0.22, 0.51; p<0.0001). Median PFS was not reached in either arm after a median follow-up duration of 28 months. The overall response rate was 85% in VEN+G arm compared to 71% in GClb arm, p=0.0007. The trial also demonstrated statistically significant improvements in rates of minimal residual disease negativity (less than one CLL cell per 104 leukocytes) in bone marrow and peripheral blood. Overall survival data were not mature at this analysis. In CLL/SLL, the most common adverse reactions (≥ 20%) for venetoclax when administered with obinutuzumab, rituximab, or as monotherapy were neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema.

In an open-label, multi-center, phase Ib study, Radford et al (2013) examined the safety and activity of obinutuzumab plus chemotherapy in relapsed/refractory follicular lymphoma in 56 patients.  Subjects received obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP; every 3 weeks for 6 to 8 cycles) or obinutuzumab plus fludarabine and cyclophosphamide (G-FC; every 4 weeks for 4 to 6 cycles).  Patients were randomly assigned to either obinutuzumab 1,600 mg on days 1 and 8 of cycle 1 followed by 800 mg on day 1 of subsequent cycles or 400 mg for all doses.  Treatment responders were eligible for obinutuzumab maintenance every 3 months for up to 2 years.  Grade 1/2 infusion-related reactions (IRRs) were the most common treatment-related adverse event (AE) (all grades: G-CHOP, 68 %; G-FC, 82 %).  Grade 3/4 IRRs were rare (7 %) and restricted to the first infusion.  All patients received the planned obinutuzumab dose.  Neutropenia was the most common treatment-related hematologic AE for G-CHOP (43 %) and G-FC (50 %).  At the end of induction, a total of 96 % (27/28) of patients who received G-CHOP (complete response [CR], 39 % [11/28]) and 93 % (26/28) of patients who received G-FC (CR, 50 % [14 of 28]) achieved responses.  The authors concluded that G-CHOP and G-FC had an acceptable safety profile with no new or unexpected AEs, but G-FC was associated with more AEs than G-CHOP.  They stated that obinutuzumab plus chemotherapy resulted in 93 % to 96 % response rates, supporting phase III investigation.

Morschhauser et al (2013) noted that obinutuzumab was superior to rituximab in human diffuse large B-cell lymphoma (DLBCL) and mantle-cell lymphoma (MCL) xenograft models.  In a phase I study by these researchers, obinutuzumab exhibited encouraging activity but no clear dose-response relationship, and few patients had aggressive histologies.  In a randomized phase II study, these investigators examined the safety and effectiveness of 2 doses of obinutuzumab in patients with heavily pre-treated DBLCL and MCL.  Patients were randomly assigned to receive 8 cycles of obinutuzumab either as a flat dose of 400 mg for all infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 to 8) or 1,600 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8.  A total of 40 patients were enrolled: 21 patients in the 400/400-mg treatment arm (DLBCL, n = 10; MCL, n = 11) and 19 patients in the 1,600/800-mg arm (DLBCL, n = 15; MCL, n = 4).  End-of-treatment response was 28 % (32 % and 24 % in the 1,600/800-mg and 400/400-mg study arms, respectively).  Best overall response rates (ORRs) were 37 % in the 1,600/800-mg arm and 24 % in the 400/400-mg study arm (DLBCL, 8 [32 %] of 25 patients; MCL, 4 [27 %] of 15 patients).  Five (20 %) of 25 rituximab-refractory patients exhibited treatment response, including 4 of 12 in the 1,600/800-mg group.  The most common AEs were IRRs, which were manageable; 3 patients had grade 3/4 IRRs; grade 3/4 neutropenia was seen in only 1 patient.  The authors concluded that obinutuzumab 1,600/800 mg achieved early steady-state concentration and clinical activity with an acceptable safety profile in relapsed/refractory DLBCL and MCL, supporting further exploration.

Cameron and McCormack (2014) stated that obinutuzumab is an intravenously administered, humanized and glyco-engineered, type II anti-CD20 monoclonal antibody for the treatment of B-cell malignancies.  It is approved in the U.S. for use in combination with chlorambucil for the first-line treatment of CLL, and has been filed for approval in the EU in this indication.  The antibody is based on GlycArt Biotechnology's (later Roche Glycart AG) proprietary GlycoMAb® technology, which uses glycol-engineered antibodies that specifically increase antibody-dependent cellular cytotoxicity and thereby increase immune-mediated target cell death.  Obinutuzumab is a type II anti-CD20 antibody that induces enhanced direct cell death.  The monoclonal antibody is in world-wide phase III development with Roche and its subsidiaries, Genentech and Chugai Pharmaceutical, as well as Biogen Idec, for DLBCL and non-Hodgkin's lymphoma (NHL) generally, and is also in phase III development in countries outside of the U.S. and EU for CLL.

An UpToDate review on “Treatment of relapsed or refractory diffuse large B cell lymphoma” (Freedman and Friedberg, 2014) states that “CLINICAL TRIALS -- Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial.  Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).  Areas of active study include novel agents such as obinutuzumab, everolimus, PI3 kinase inhibitors, aurora A kinase inhibitors, and syk inhibitors”.

In the phase II part of the phase I/II GAUGUIN study, Salles et al (2013) evaluated the safety and effectiveness of 2 different doses of obinutuzumab in patients with relapsed/refractory indolent NHL.  Patients were randomly assigned to receive 8 cycles of obinutuzumab as a flat dose of 400 mg on days 1 and 8 of cycle 1 and also on day 1 of cycles 2 to 8 (400/400 mg) or 1,600 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8 (1,600/800 mg).  A total of 40 patients were enrolled, including 34 with follicular lymphoma; 38 of 40 patients had previously received rituximab and 22 of 40 were rituximab refractory.  The ORR at the end of treatment was 55 % (95 % confidence interval [CI]: 32 % to 76%) in the 1,600/800-mg group (9 % complete responders) and 17 % (95 % CI: 4 % to 41 %) in the 400/400-mg group (no complete responders).  Five of 10 rituximab-refractory patients had an end-of-treatment response in the 1,600/800-mg group versus 1 of 12 in the 400/400-mg group.  Median progression-free survival (PFS) was 11.9 months in the 1,600/800-mg group (range of 1.8 to 33.9+ months) and 6.0 months in the 400/400-mg group (range of 1.0 to 33.9+ months).  The most common AEs were IRRs seen in 73 % of patients, but only 2 patients had grade 3 to 4 IRRs (both in the 1,600/800-mg group).  No IRRs were considered serious, and no patients withdrew for IRRs.  The authors concluded that the 1,600/800-mg dose schedule of obinutuzumab has encouraging activity with an acceptable safety profile in relapsed/refractory indolent NHL.

Owen and Stewart (2014) analyzed data for the use of obinutuzumab in the treatment of CD20(+) lympho-proliferative disorders with a focus on CLL.  Targeted therapy against CD20 with the mAb rituximab led to significant improvements in survival for patients with B-cell NHL and is the current mainstay of treatment for CD20(+) malignancies.  Despite this, many patients relapse or become refractory after rituximab-containing therapies, so efforts have been made to develop better anti-CD20 mAbs.  Obinutuzumab recently demonstrated superiority over rituximab in the only published phase III study comparing the 2 antibodies.  The authors concluded that the demonstration of superiority of obinutuzumab over rituximab in the CLL11 phase III study is potentially practice-changing.  Obinutuzumab has also proven safe and effective in CD20(+) NHL in phase I/II studies and results of phase III studies in NHL are eagerly awaited.

Acute Lymphoblastic Leukemia and Burkitt Lymphoma

Awasthi and colleagues (2015) noted that CD20 is expressed in approximately 100 % of children and adolescents with Burkitt lymphoma (BL) and 40 % with precursor B-cell acute lymphoblastic leukemia (pre-B-ALL).  These researchers evaluated the anti-tumor activity of obinutuzumab versus rituximab against rituximab-resistant (Raji 4RH) and rituximab-sensitive (Raji) BL and pre-B-ALL (U698-M) cells in-vitro and in human BL or Pre-B-ALL xenografted mice.  They demonstrated that obinutuzumab compared to rituximab significantly enhanced cell death against Raji 35.6 ± 3.1 % versus 25.1 ± 2.0 %, (p = 0.001), Raji4RH 19.7 ± 2.2 % versus 7.9 ± 1.5 % (p = 0.001) and U-698-M 47.3 ± 4.9% versus 23.2 ± 0.5 % (p = 0.001), respectively.  Obinutuzumab versus rituximab also induced a significant increase in antibody-dependent cellular cytotoxicity (ADCC) with K562-IL15-41BBL expanded NK cells against Raji 73.8 ± 8.1 % versus 56.81 ± 4.6 % (p = 0.001), Raji-4RH 40.0 ± 1.6 % versus 0.5 ± 1.1 % (p = 0.001) and U-698-M 70.0 ± 1.6 % versus 45.5 ± 0.1 % (p = 0.001), respectively.  Overall survival in tumor xenografted mice receiving 30 mg/kg of obinutuzumab was significantly increased when compared to those receiving 30 mg/kg of rituximab in BL; Raji (p = 0.05), Raji4RH (p = 0.02) and U698-M (p = 0.03), respectively.  These pre-clinical data suggested that obinutuzumab is significantly superior to rituximab in inducing cell death, ADCC and against rituximab-sensitive/-resistant BL and pre-B-ALL xenografted mice.  The authors concluded that taken together, these pre-clinical results provided evidence to suggest that future investigation of obinutuzumab is warranted in patients with relapsed/refractory CD20(+) BL and/or pre-B-ALL.

Wei and colleagues (2017) the last 10 years witnessed the rapid development of adult B-lineage ALL treatment.  Beyond the development of chemotherapy regimens, immunotherapy is starting a new era with unprecedented CR rate.  Targeting B-lineage-specific surface markers such as CD19, CD20, CD22, or CD52, immunotherapy has been demonstrating promising clinical results.  Among the immunotherapeutic methods, naked monoclonal antibodies (mAbs), antibody-drug conjugate (ADC), bi-specific T cell engager (BiTE), and chimeric antigen receptor (CAR) T cells are the main types.  These investigators examined the emerging pre-clinical and clinical development on
  1. anti-CD20 naked mAbs rituximab, ofatumumab, and obinutuzumab;
  2. anti-CD19 ADCs SAR3419 and SGN-CD19A and anti-CD19 BiTE blinatumomab;
  3. anti-CD22 naked mAb epratuzumab and anti-CD22 ADC inotuzumab ozogamicin;
  4. anti-CD52 naked mAb alemtuzumab; and
  5. anti-CD19 CAR T cells.

Follicular Lymphoma/Gastric MALT Lymphoma/Nodal Marginal Zone Lymphoma/Non-Gastric MALT Lymphoma/Primary Cutaneous B-cell Lymphoma/Splenic Marginal Zone Lymphoma

On February 26, 2016, the UFDA approved Gazyva (obinutuzumab) plus bendamustine chemotherapy followed by Gazyva alone as a new treatment for people with follicular lymphoma who did not respond to a Rituxan (rituximab)-containing regimen, or whose follicular lymphoma returned after such treatment.  The approval is based on results from the phase III GADOLIN study, which showed that, in people with follicular lymphoma whose disease progressed during or within 6 months of prior rituximab-based therapy, obinutuzumab plus bendamustine followed by obinutuzumab alone demonstrated a 52 % reduction (hazard ratio [HR] = 0.48, 95 % CI: 0.34 to 0.68, p < 0.0001) in the risk of disease worsening or death (PFS), compared to bendamustine alone, as assessed by an independent review committee (IRC).  The supplemental Biologics License Application based on these data was granted Priority Review, a designation granted to medicines that the FDA has determined to have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease.

Autoimmune Bullous Diseases

Huang and colleagues (2016) stated that the conventional treatment for patients with pemphigus vulgaris (PV) centers on global immunosuppression, such as the use of steroids and other immunosuppressive drugs, to decrease titers of anti-desmoglein autoantibodies responsible for the acantholytic blisters.  Global immunosuppressants, however, cause serious side effects.  The emergence of anti-CD20 biologic medications, such as rituximab (RTX), as an adjunct to conventional therapy has shifted the focus to targeted destruction of autoimmune B-cells.  Next-generation biologic medications with improved modes of delivery, pharmacology, and side effect profiles are constantly being developed, adding to the diversity of options for PV treatment.  The authors reviewed promising monoclonal antibodies, including veltuzumab, obinutuzumab (OBZ), ofatumumab, ocaratuzumab, PRO131921, and belimumab.

De and co-workers (2017) stated that therapeutics of autoimmune bullous disease has seen a major shift of focus from more global immunosuppression to targeted immunotherapy.  Anti-CD20 monoclonal antibody RTX revolutionized the therapeutics of autoimmune bullous disease particularly pemphigus.  Although it is still being practiced off-label, evidences in the form of RCT and meta-analysis are now available.  Other novel anti-CD20 monoclonal antibodies like ofatumumab, veltuzumab, and ocrelizumab, tositumomab or OBZ may add to the therapeutic options in coming days.  Beyond anti-CD20 monoclonal antibodies other options that show promise at least in select scenario are omalizumab, TNF inhibitors, plasmapheresis and intravenous immunoglobulin.

Diffuse Large B-Cell Lymphoma (DLBCL)

Vitolo and colleagues (2017) stated that RTX plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy is the standard of care in previously untreated diffuse large B-cell lymphoma (DLBCL).  Obinutuzumab is a glycol-engineered, type II, anti-CD20 monoclonal antibody; and GOYA was a randomized phase III clinical trial that compared G-CHOP with R-CHOP in patients with previously untreated advanced-stage DLBCL.  Patients (n = 1,418) were randomly assigned to receive 8 21-day cycles of OBZ (n = 706) or RTX (n = 712), plus 6 or 8 cycles of CHOP.  Primary end-point was investigator-assessed PFS.   After median observation of 29 months, the number of investigator-assessed PFS events was similar between OBZ (201; 28.5 %) and RTX (215; 30.2 %), stratified HR was 0.92 (95 % CI: 0.76 to 1.11; p = 0.39), and 3-year PFS rates were 70 % and 67 %, respectively.  Secondary end-points of independently reviewed PFS, other time-to-event end-points, and tumor response rates were similar between arms.  In exploratory subgroup analyses, patients with germinal-center B cell-like subtype had a better PFS than did patients with activated B cell-like subtype, irrespective of treatment.  Frequencies of grade-3 to grade-5 AEs (73.7 % versus 64. 7%, respectively) and serious AEs (42.6 % versus 37.6 %, respectively) were higher with OBZ-CHOP compared with RTX-CHOP.  Fatal AE frequencies were 5.8 % for OBZ-CHOP and 4.3 % for RTX-CHOP.  The most common AEs were neutropenia (OBZ-CHOP, 48.3 %; RTX-CHOP, 40.7 %), infusion-related reactions (OBZ-CHOP, 36.1 %; RTX-CHOP, 23.5 %), nausea (OBZ-CHOP, 29.4 %; RTX-CHOP, 28.3 %), and constipation (OBZ-CHOP, 23.4 %; RTX-CHOP, 24.5 %).  The authors concluded that OBZ-CHOP did not improve PFS compared with RTX-CHOP in patients with previously untreated DLBCL; AEs reported with OBZ were consistent with the known safety profile.  Moreover, they stated that biomarker analyses may help define a future role for OBZ in DLBCL.

Yasuhiro and associates (2017) stated that the activated B-cell DLBCL (ABC-DLBCL) correlates with poor prognosis.  The B-cell receptor signaling pathway is known to be dysregulated in NHL/CLL and given Bruton's tyrosine kinase (BTK) is a down-stream mediator of BCR signaling, BTK constitutes an interesting and obvious therapeutic target.  Given the high potency and selectivity of the BTK inhibitor, ONO/GS-4059, it was hypothesized that, the anti-tumor activity of ONO/GS-4059 could be further enhanced by combining it with the anti-CD20 Abs, RTX or OBZ.  ONO/GS-4059 combined with OBZ or RTX was significantly better than the respective monotherapy with tumor growth inhibition (TGI) of 90 % for the OBZ combination and 86 % for the RTX combination.  In contrast, ibrutinib (PCI-32765) combined with RTX did not result in improved efficacy compared with respective monotherapy.  The authors concluded that these data indicated that the combination of ONO/GS-4059 with R and particularly G may be an effective treatment for ABC-DLBCL.  These preliminary findings need to be validated by well-designed studies.

Lymphoma of the Cervix

Hilal and colleagues (2016) stated that lymphoma of the uterine cervix (LUCX) is rare and may occur as a primary or secondary manifestation of this disease.  Clinical and cytological presentations of LUCX vary and establishing diagnosis is often difficult.  Surgery followed by radiation or chemotherapy is the mainstay of treatment.  These investigators presented the case of a 73-year old woman with recurrent pathological PAP smears of the cervix and a history of CLL 15 years ago.  Colposcopy of the cervix showed no acetowhite lesion and a conization was performed.  Histology revealed endo-cervical lymphoid cells, specified as low-malignant B-NHL of the cervix based on the expression of CD5, CD20, and CD23, while CD10 and cyclin D1 were negative.  The diagnosis was confirmed by flow cytometry of peripheral blood.  Staging revealed enlarged iliacal, para-aortic, mediastinal, cervical, subclavicular, and inguinal lymph nodes and hepatosplenomegaly.  Bone marrow analysis confirmed lymphoid infiltration consistent with B-cell lymphoma.  The patient was scheduled for a combined immuno-chemotherapy with obinutuzumab and chlorambucil.  In a Medline literature search, a total of 246 cases of LUCX were identified; 185 cases were primary and 61 cases were secondary manifestations of LUCX.  With a mean follow-up time of 38 months, overall survival (OS) was 81 %.  The authors concluded that LUCX is rare and has distinct clinical and histological features; LUCX is usually treated with local surgical excision followed by radiotherapy or chemotherapy.

Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2019) does not list lymphoma of the cervix as a recommended indication of obinutuzumab.

Rheumatoid Arthritis and Systemic Lupus Erythematosus

Reddy and colleagues (2017) noted that a proportion of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients treated with standard doses of RTX display inefficient B-cell deletion and poor clinical responses that can be augmented by delivering higher doses, indicating that standard-dose RTX is a sub-optimal therapy in these patients.  These investigators examined if better responses could be achieved with mechanistically different anti-CD20 mAbs.  They compared RTX with OBZ in a series of in-vitro assays measuring B-cell cytotoxicity in RA and SLE patient samples.  These researchers found that OBZ was at least 2-fold more efficient than RTX at inducing B-cell cytotoxicity in in-vitro whole blood assays.  Dissecting this difference, these researchers found that RTX elicited more potent complement-dependent cellular cytotoxicity than OBZ.  In contrast, OBZ was more effective at evoking Fc gamma receptor-mediated effector mechanisms, including activation of NK cells and neutrophils, probably due to stronger interaction with Fc gamma receptors and the ability of OBZ to remain at the cell surface following CD20 engagement, whereas RTX became internalized; OBZ was also more efficient at inducing direct cell death.  This was true for all CD19 + B cells as a whole and in naive (IgD + CD27 - ) and switched (IgD - CD27 + ) memory B cells specifically, a higher frequency of which is associated with poor clinical response after RTX.  The authors concluded that these in-vitro findings provided a mechanistic basis for resistance to rituximab-induced B-cell depletion, and for considering obinutuzumab as an alternative B-cell depleting agent in RA and SLE.  These findings need to be further investigated in clinical trials.

Anti-MAG Demyelinating Neuropathy

Rakocevic and associates (2018) noted that anti-MAG demyelinating neuropathy is difficult to treat.  All immunotherapies have failed except for rituximab, a chimeric B-cell–depleting monoclonal antibody against CD20, that helped up to 40 % of patients based on 2 controlled and several uncontrolled series.  Because the majority of these patients are left disabled, stronger anti–B-cell agents might be promising.  These researchers described clinical response and autoantibody changes after treatment with obinutuzumab, a new generation of humanized anti-CD20 monoclonal antibodies, in 2 patients with anti-MAG neuropathy who continued to worsen despite multiple courses of rituximab.  Obinutuzumab exerts greater peripheral and lymphoid B-cell depletion and might be more effective in rituximab-refractory patients.  The authors concluded that these preliminary results, even in a limited number of 2 patients, suggested that the IgM anti-MAG antibodies, despite being pathogenic, did not appear to correlate with clinical response.  Whether this was related to these patients' advanced disease and severe axonal degeneration or to ineffectiveness of obinutuzumab was unclear.  The good tolerance of the drug, however, the more profound induction of B-cell depletion, and effect on antibodies, as demonstrated with normalization of IgM and anti-MAG titers, suggested that obinutuzumab might still be considered as an early treatment of this difficult-to-treat neuropathy.   This was an observational study without controls and provided Class IV evidence that obinutuzumab is safe to use in patients with IgM anti-MAG demyelinating neuropathy.

B-Cell Prolymphocytic Leukemia

Hew and colleagues (2018) reported on the case of a patient with B-cell prolymphocytic leukemia who was successfully treated with the novel humanized monoclonal antibody obinutuzumab.  This patient was previously treated with the combination of rituximab and bendamustine and had recurrent infusion reactions.  Her treatment with rituximab and bendamustine was discontinued when she developed disease progression after 3 cycles of therapy.  She was then treated with obinutuzumab 1,000 mg on day 1 of every cycle and chlorambucil 0.5 mg/kg on days 1 and 15 every 28 days to which she had greater tolerability.  After 4 cycles of treatment, she had resolution of her clinical symptoms, massive splenomegaly, and normalization of her white blood cell count.  The authors concluded that more studies are needed to examine the efficacy of this regimen in patients with B-cell prolymphocytic leukemia and the optimal length of therapy.

NCCN Recommendations

NCCN Drugs and Biologics Compendium (NCCN, 2019) recommends obinutuzumab for the following:

  • Follicular lymphoma (grade 1 - 2) [2A]
     
    • Preferred first-line therapy for stage I (≥7 cm), contiguous stage II (≥7 cm), non-contiguous stage II disease (2B for first-line therapy in combination with involved site radiation therapy), or for patients with indications for treatment with stage III or IV disease in combination with 
       
      • CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen
      • CVP (cyclophosphamide, vincristine, and prednisone) regimen
      • bendamustine 
         
    • Preferred second-line or subsequent therapy (if not previously given as first-line) for refractory or progressive disease in patients with indications for treatment in combination with
       
      • CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen
      • CVP (cyclophosphamide, vincristine, and prednisone) regimen
      • bendamustine
         
    • Maintenance therapy 
       
      • as optional first-line consolidation or extended dosing
      • as optional second-line consolidation or extended dosing for rituximab-refractory disease
      • can be considered for patients with histologic transformation to diffuse large B-cell lymphoma that is coexisting with extensive follicular lymphoma who achieve a complete response to chemoimmunotherapy
         
  • Gastric MALT lymphoma [2A]
     
    • Second-line or subsequent therapy for recurrent or progressive disease in combination with bendamustine in patients with indications for treatment
    • Maintenance therapy as second-line consolidation or extended dosing in rituximab refractory patients treated with obinutuzumab and bendamustine regimen for recurrent disease
       
  • Nodal Marginal Zone Lymphoma [2A]
     
    • Second-line or subsequent therapy for refractory or progressive disease in combination with bendamustine in patients with indications for treatment
    • Maintenance therapy as second-line consolidation or extended dosing in rituximab refractory patients treated with obinutuzumab and bendamustine regimen for recurrent disease
       
  • Nongastric MALT Lymphoma [2A]
     
    • Second-line or subsequent therapy for refractory or progressive disease in combination with bendamustine in patients with indications for treatment
    • Maintenance therapy as second-line consolidation or extended dosing in rituximab refractory patients treated with obinutuzumab and bendamustine regimen for recurrent disease
       
  • Splenic Marginal Zone Lymphoma [2A]
     
    • Second-line or subsequent therapy for refractory or progressive disease in combination with bendamustine in patients with indications for treatment
    • Maintenance therapy as second-line consolidation or extended dosing in rituximab refractory patients treated with obinutuzumab and bendamustine regimen for recurrent disease.  

  • For the B-Cell lymphomas, the Compendium also states obinutuzumab can be used as a substitute for rituximab in patients experiencing rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis.
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
     
    • First-line therapy for CLL/SLL without del(17p)/TP53 mutation
       
      • in combination with ibrutinib or with venetoclax or with chlorambucil in frail patients with significant comorbidity (not able to tolerate purine analogs) or age ≥65 years and younger patients with significant comorbidities 
      • in combination with venetoclax in patients <65 years without significant comorbidities
      • in combination with bendamustine in patients age ≥65 years and younger patients with or without significant comorbidities who have indications for treatment (not recommended for frail patients)
      • as a single agent in frail patients with significant comorbidity (not able to tolerate purine analogs) or age ≥65 years and younger patients with significant comorbidities.
         
      (2B in combination with ibrutinib or as a single agent for frail patients or age ≥65 years and younger with significant comorbidities or in combination with venetoclax for patients age <65 years without significant comorbidities).

 

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:

96413 Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug
+96415     each additional hour (List separately in addition to code for primary)

HCPCS codes covered if selection criteria are met :

J9301 Injection, obinutuzumab, 10 mg

Other HCPCS codes related to the CPB:

Ibrutinib, venetoclax - no specific code :

J7512 Prednisone, immediate release or delayed release, oral, 1 mg
J8530 Cyclophosphamide; oral, 25 mg
J9000 Injection, doxorubicin HCl, 10 mg
J9001 Injection, doxorubicin HCl, all lipid formulations, 10 mg
J9033 Injection, bendamustine HCL, 1 mg
J9034 Injection, bendamustine hcl (bendeka), 1 mg
J9070 Cyclophosphamide, 100 mg
J9312 Injection, rituximab, 10 mg
J9370 Vincristine sulfate, 1 mg
S0172 Chlorambucil, oral, 2mg

ICD-10 codes covered if selection criteria are met:

C82.00 - C82.99 Follicular lymphoma
C83.00 - C83.09 Small cell B-cell lymphoma [splenic marginal zone lymphoma]
C83.10 - C83.19 Mantle cell lymphoma
C83.30 - C83.39 Diffuse large B-cell lymphoma
C83.70 - C83.79 Burkitt lymphoma
C84.Z0 - C84.99 Other and unspecified mature T/NK-cell lymphoma [primary cutaneous B-cell lymphoma]
C85.10 - C85.19 Unspecified B-cell lymphoma
C85.20 - C85.29 Mediastinal (thymic) large B-cell lymphoma
C85.80 - C85.89 Other specified types of non-Hodgkin lymphoma [primary cutaneous B-cell lymphoma]
C86.0 - C86.6 Other specified types of T/NK-cell lymphoma [primary cutaneous B-cell lymphoma]
C88.4 Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [primary cutaneous marginal zone lymphoma]
C91.10 - C91.12 Chronic lymphocytic leukemia of B-cell type [small lymphocytic lymphoma]
D47.Z1 Post-transplant lymphoproliferative disorder (PTLD)
D47.Z2 Castleman disease

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

B16.0 - B16.9 Acute hepatitis B
B18.0 - B18.1 Chronic viral hepatitis B
C83.10 - C83.19 Mantle cell lymphoma
C83.30 - C83.39 Diffuse large B-cell lymphoma
C83.70 - C83.79 Burkitt lymphoma
C85.20 - C85.29 Mediastinal (thymic) large B-cell lymphoma
C85.93 Non-Hodgkin lymphoma, unspecified, intra-abdominal lymph nodes [lymphoma of the cervix]
C91.00 - C91.02 Acute lymphoblastic leukemia [ALL]
C91.30 - C91.33 Prolymphocytic leukemia of B-cell type
G62.89 Other specified polyneuropathies [MAG demyelinating neuropathy]
M05.00 - M08.48 Rheumatoid arthritis with rheumatoid factor
M32.0 - M32.9 Systemic lupus erythematosus (SLE).
L10.00 - L14 Bullous disorders

ICD-10 codes covered if selection criteria are met as a substitute for rituximab:

L10.81 Paraneoplastic pemphigus
L13.9 Bullous disorder, unspecified
L30.2 Cutaneous autosensitization
L51.1 Stevens-Johnson syndrome
L51.2 Toxic epidermal necrolysis [Lyell]
L51.3 Stevens-Johnson syndrome-toxic epidermal necrolysis overlap syndrome
L81.7 Pigmented purpuric dermatosis

The above policy is based on the following references:

  1. Jaglowski SM, Alinari L, Lapalombella R et al. The clinical application of monoclonal antibodies in chronic lymphocytic leukemia. Blood. 2010;116(19):3705-3714.
  2. Laprevotte E, Ysebaert L, Klein C, et al. Endogenous IL-8 acts as a CD16 co-activator for natural killer-mediated anti-CD20 B cell depletion in chronic lymphocytic leukemia. Leuk Res. 2013;37(4):440-446.
  3. National Cancer Institute (NCI). FDA approval for obinutuzumab. Brand name: Gazyva. Cancer Drug Information. Bethesda, MD: NCI; November 1, 2013.
  4. U.S. Food and Drug Administration (FDA). FDA approves Gazyva for chronic lymphocytic leukemia. FDA News Release. Silver Spring, MD: FDA; November 1, 2013.
  5. Genentech, Inc. Gazyva (obinutuzumab). Prescribing Information. Reference ID: 3400019. South San Francisco, CA: Genentech; revised November 2013.
  6. Radford J, Davies A, Cartron G, et al. Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: Results of the GAUDI study (BO21000). Blood. 2013;122(7):1137-1143.
  7. Morschhauser FA, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: Results from the phase II GAUGUIN study. J Clin Oncol. 2013;31(23):2912-2919.
  8. Salles GA, Morschhauser F, Solal-Céligny P, et al. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: Results from the phase II GAUGUIN study. J Clin Oncol. 2013;31(23):2921-29266.
  9. Freedman AS, Friedberg JW. Treatment of relapsed or refractory diffuse large B cell lymphoma. UpToDate [serial online]. Waltham, MA: UpToDate; reviewed August 2014.
  10. Cameron F, McCormack PL. Obinutuzumab: First global approval. Drugs. 2014;74(1):147-154.
  11. National Comprehensive Cancer Network (NCCN). Obinutuzumab. NCCN Drugs & Biologics Compendium. Fort Washington, PA: NCCN; 2014.
  12. Owen CJ, Stewart DA. Obinutuzumab for B-cell malignancies. Expert Opin Biol Ther. 2014;14(8):1197-1205.
  13. National Comprehensive Cancer Network (NCCN). Obinutuzumab. NCCN Drug & Biologics Compendium. Fort Washington, PA: NCCN; 2017.
  14. Sehn LH, Goy A, Offner FC, et al. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: Final analysis of the GAUSS study. J Clin Oncol. 2015;33(30):3467-3474.
  15. Cartron G, Hourcade-Potelleret F, Morschhauser F, et al. Rationale for optimal obinutuzumab/GA101 dosing regimen in B-cell non-Hodgkin lymphoma. Haematologica. 2016;101(2):226-234.
  16. Awasthi A, Ayello J, Van de Ven C, et al. Obinutuzumab (GA101) compared to rituximab significantly enhances cell death and antibody-dependent cytotoxicity and improves overall survival against CD20(+) rituximab-sensitive/-resistant Burkitt lymphoma (BL) and precursor B-acute lymphoblastic leukaemia (pre-B-ALL): Potential targeted therapy in patients with poor risk CD20(+) BL and pre-B-ALL. Br J Haematol. 2015;171(5):763-775.
  17. U.S. Food and Drug Administration (FDA). Obinutuzumab. Approved Drugs. Silver Spring, MD: FDA; February 26, 2016.
  18. Cheah CY, Seymour JF, Wang ML. Mantle cell lymphoma. J Clin Oncol. 2016;34(11):1256-1269.
  19. Huang A, Madan RK, Levitt J. Future therapies for pemphigus vulgaris: Rituximab and beyond. J Am Acad Dermatol. 2016 r;74(4):746-753.
  20. Hilal Z, Hartmann F, Dogan A, et al. Lymphoma of the cervix: Case report and review of the literature. Anticancer Res. 2016;36(9):4931-4940.
  21. Wei G, Wang J, Huang H, Zhao Y. Novel immunotherapies for adult patients with B-lineage acute lymphoblastic leukemia. J Hematol Oncol. 2017;10(1):150.
  22. De A, Ansari A, Sharma N, Sarda A. Shifting focus in the therapeutics of immunobullous disease. Indian J Dermatol. 2017;62(3):282-290.
  23. Yasuhiro T, Sawada W, Klein C, et al. Anti-tumor efficacy study of the Bruton's tyrosine kinase (BTK) inhibitor, ONO/GS-4059, in combination with the glycoengineered type II anti-CD20 monoclonal antibody obinutuzumab (GA101) demonstrates superior in vivo efficacy compared to ONO/GS-4059 in combination with rituximab. Leuk Lymphoma. 2017;58(3):699-707.
  24. National Comprehensive Cancer Network (NCCN). Obinutuzumab. NCCN. Drugs & Biologics Compendium. Fort Washington, PA: NCCN; 2019.
  25. Reddy V, Klein C, Isenberg DA, et al. Obinutuzumab induces superior B-cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples. Rheumatology (Oxford). 2017;56(7):1227-1237.
  26. Vitolo U, Trneny M, Belada D, et al. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2017;35(31):3529-3537.
  27. Falchi L, Ferrajoli A, Jacobs I, Nava-Parada P. An Evidence-based review of anti-CD20 antibody-containing regimens for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia, diffuse large B-cell lymphoma, or follicular lymphoma. Clin Lymphoma Myeloma Leuk. 2018;18(8):508-518.
  28. Rakocevic G, Martinez-Outschoorn U, Dalakas MC. Obinutuzumab, a potent anti-B-cell agent, for rituximab-unresponsive IgM anti-MAG neuropathy. Neurol Neuroimmunol Neuroinflamm. 2018;5(4):e460.
  29. Hew J, Pham D, Matthews Hew T, Minocha V. A novel treatment with obinutuzumab-chlorambucil in a patient with B-cell prolymphocytic leukemia: A case report and review of the literature. J Investig Med High Impact Case Rep. 2018;6:2324709618788674.
  30. U.S. Food and Drug Administration (FDA). FDA approves venetoclax for CLL and SLL. FDA News Release. Silver Spring, MD: FDA; May 15, 2019.
  31. AbbVie Inc. Venclexta (venetoclax tablets) for oral use. Prescribing Information. North Chicaglo, IL: AbbVie; revised May 2019.
  32. National Comprehensive Cancer Network (NCCN). Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. NCCN Clinical Practice Guidelines in Oncology, version 5.2019. Fort Washington, PA: NCCN; 2019. 
  33. National Comprehensive Cancer Network (NCCN). B-Cell Lymphomas. NCCN Clinical Practice Guidelines in Oncology, version 4.2019. Fort Washington, PA: NCCN; 2019.
  34. Genentech, Inc. Gazyva (obinutuzumab) injection, for intravenous use. Prescribing Information. South San Francisco, CA: Genentech; revised November 2017.