Obinutuzumab (Gazyva)

Number: 0877

Table Of Contents

Policy Applicable CPT / HCPCS / ICD-10 Codes Background References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses obinutuzumab (Gazyva) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

1. Criteria for Initial Approval

   Aetna considers obinutuzumab (Gazyva) medically necessary for treatment of any of the following indications:

   1. Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)

      1. For the treatment of chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) as a single agent or in combination with acalabrutinib, venetoclax, bendamustine or chlorambucil; or
      2. In combination with high-dose methylprednisolone for the treatment of CLL/SLL when Bruton Tyrosine Kinase inhibitor (e.g., acalabrutinib) and venetoclax are not available or contraindicated or rapid disease de-bulking is needed.

   2. B-Cell Lymphomas

      1. Follicular Lymphoma (FL)

         For the treatment of follicular lymphoma (up to 30 months total) when any of the following criteria are met:

         1. The requested medication will be used in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen, CVP (cyclophosphamide, vincristine and prednisone) regimen, or bendamustine as first-line therapy; or
         2. The requested medication will be used as a single agent or in combination with lenalidomide, bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CVP (cyclophosphamide, vincristine, and prednisone) for subsequent therapy; or
         3. The requested medication will be used as maintenance therapy as a single agent; or
         4. The requested medication will be used as a substitute for rituximab in members experiencing intolerance or rare complications from rituximab such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis; or
         5. The requested medication will be used in combination with zanubrutinib (Brukinsa) as third line and subsequent therapy.

      2. Extranodal Marginal Zone Lymphoma and Splenic Marginal Zone Lymphoma

         For the treatment of extranodal marginal zone lymphoma (gastric and non-gastric MALT lymphoma) or splenic marginal zone lymphoma when any of the following criteria are met:

         1. The requested medication will be used as subsequent therapy in combination with bendamustine or lenalidomide; or
         2. The requested medication be used as maintenance therapy when the member has been previously treated with the requested medication and bendamustine; or
         3. The requested medication is used as a substitute for rituximab in members experiencing intolerance or rare complications from rituximab such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis;

      3. Nodal Marginal Zone Lymphoma

         For the treatment of nodal marginal zone lymphoma when any of the following criteria are met:

         1. The requested medication will be used as first-line therapy in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen, CVP (cyclophosphamide, vincristine and prednisone) regimen, or bendamustine; or
         2. The requested medication will be used as subsequent therapy in combination with bendamustine or lenalidomide; or
         3. The requested medication be used as maintenance therapy when the member has been previously treated with the requested medication and bendamustine; or
         4. The requested medication is used as a substitute for rituximab in members experiencing intolerance or rare complications from rituximab such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis;

      4. Histologic Transformation of Indolent Lymphomas to Diffuse Large B-Cell Lymphoma, Diffuse Large B-Cell Lymphoma, High-Grade B-Cell Lymphomas

         (including high-grade B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 [double/triple hit lymphoma], high-grade B-cell lymphoma, not otherwise specified), Burkitt Lymphoma, HIV-Related B-Cell Lymphomas, Post-Transplant Lymphoproliferative Disorders, and Castleman’s Disease

         For the treatment of histologic transformation of indolent lymphomas to diffuse large B-cell lymphoma, diffuse large B-cell lymphoma, high grade B-cell lymphomas (including high grade B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 [double/triple hit lymphoma], high-grade B-cell lymphoma, not otherwise specified), Burkitt lymphoma, HIV-related B-cell lymphomas, post-transplant lymphoproliferative disorders, or Castleman’s disease when the requested medication is used as a substitute for rituximab in members experiencing intolerance or rare complications from rituximab such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis.

      5. B-Cell Lymphomas when used as pre-treatment with glofitamab (Columvi)

         For treatment of diffuse large B-cell lymphomat, high-grade B-cell lymphomas, histologic transformation of indolent lymphomas to diffuse large B-cell lymphoma, HIV-related B-cell lymphomas and post-transplant lymphoproliferative disorders when used as single agent pre-treatment for up to 1 dose in cycle 1 of glofitamab therapy.

      6. Mantle Cell Lymphoma

         For mantle cell lymphoma when either of the following criteria are met:

         1. The requested medication will be used as induction therapy for TP53 mutated disease and in combination with Venclexta (venetoclax) and Brukinsa (zanubrutinib); or
         2. The requested medication is used as a substitute for rituximab in members experiencing intolerance or rare complications from rituximab such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis.

   3. Hairy Cell Leukemia

      In combination with vemurafenib as initial therapy for treatment of hairy cell leukemia in members who are unable to tolerate purine analogs.

   Aetna considers all other indications as experimental, investigational, or unproven.

2. Continuation of Therapy

   1. Follicular Lymphoma (FL)

      Aetna considers continuation of obinutuzumab (Gazyva) therapy (up to 30 months total) in members for follicular lymphoma when there is no evidence of unacceptable toxicity or disease progression while on the current regimen;

   2. B-Cell Lymphomas when used as pre-treatment with glofitamab (Columvi)

      Aetna considers continuation of obinutuzumab (Gazyva) therapy for all members (including new members) who meet all initial medical necessity selection criteria.

   3. All other indications

      Aetna considers continuation of obinutuzumab (Gazyva) therapy in members for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Note: 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.

Dosage and Administration

Obinutuzumab (Gazyva) is available as a 1,000 mg/40 mL (25 mg/mL) single-dose vial for intravenous infusion only. Do not administer as an intravenous push or bolus.

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

Chronic lymphocytic leukemia (CLL): is 100 mg on day 1 and 900 mg on day 2 of Cycle 1, 1000 mg on day 8 and 15 of Cycle 1, and 1000 mg on day 1 of Cycles 2 – 6.

Follicular lymphoma (FL): 1000 mg on day 1, 8 and 15 of Cycle 1, 1000 mg on day 1 of Cycles 2 – 6 or Cycles 2 – 8; and then 1000 mg every 2 months for up to 2 years.

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Source: Genentech, 2022

Experimental, Investigational, or Unproven

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

• Acute lymphoblastic leukemia
• Anti-MAG demyelinating neuropathy
• B-cell prolymphocytic leukemia
• Immune thrombotic thrombocytopenic purpura
• Lupus nephritis
• Lymphoma of the cervix
• Nephrotic syndrome
• Rheumatoid arthritis
• Systemic lupus erythematosus
• Waldenstrom macroglobulinemia.

Aetna considers combined obinutuzumab (Gazyva) and pixantrone for relapsed aggressive lymphoma experimental, investigational, or unproven.

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

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, acalabrutinib (Calquence), lenalidomide, pixantrone, Vemurafenib, Zanubrutinib (Brukinsa)- no specific code J1010 Injection, methylprednisolone acetate, 1 mg J2919 Injection, methylprednisolone sodium succinate, 5 mg J7512 Prednisone, immediate release or delayed release, oral, 1 mg J8530 Cyclophosphamide; oral, 25 mg J9000 Injection, doxorubicin HCl, 10 mg J9033 Injection, bendamustine HCL, 1 mg J9034 Injection, bendamustine hcl (bendeka), 1 mg J9056 Injection, bendamustine hydrochloride (vivimusta), 1 mg J9058 Injection, bendamustine hydrochloride (apotex), 1 mg J9059 Injection, bendamustine hydrochloride (baxter), 1 mg J9070 Cyclophosphamide, 100 mg J9071 Injection, cyclophosphamide, (auromedics), 5 mg J9072 Injection, cyclophosphamide, (dr. reddy’s), 5 mg J9073 Injection, cyclophosphamide (ingenus), 5 mg J9074 Injection, cyclophosphamide (sandoz), 5 mg J9075 Injection, cyclophosphamide, not otherwise specified, 5mg J9286 Injection, glofitamab-gxbm, 2.5 mg J9312 Injection, rituximab, 10 mg J9370 Vincristine sulfate, 1 mg J9371 Injection, vincristine sulfate liposome, 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] [gastric and non-gastric MALT lymphoma] C91.10 – C91.12 Chronic lymphocytic leukemia of B-cell type [small lymphocytic lymphoma] C91.40 – C91.42 Hairy cell leukemia 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 C85.20 – C85.29 Mediastinal (thymic) large B-cell lymphoma C85.93 Non-Hodgkin lymphoma, unspecified, intra-abdominal lymph nodes [lymphoma of the cervix] C88.0 Waldenstrom macroglobulinemia C91.00 – C91.02 Acute lymphoblastic leukemia [ALL] C91.30 – C91.33 Prolymphocytic leukemia of B-cell type D69.3 Immune thrombocytopenic purpura 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). N04.0 – N04.A Nephrotic syndrome 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

Background

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

• Chronic Lymphocytic Leukemia (CLL)

  Gazyva, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated CLL.

• Follicular Lymphoma

  • Gazyva, in combination with bendamustine followed by Gazyva monotherapy, is indicated for the treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen.
  • Gazyva, in combination with chemotherapy followed by Gazyva monotherapy in patients achieving at least a partial remission, is indicated for the treatment of adult patients with previously untreated stage II bulky, III or IV follicular lymphoma.

Compendial Uses

• Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
• Follicular lymphoma
• Marginal zone lymphomas
  • Extranodal (gastric and non-gastric MALT lymphoma) marginal zone lymphoma
  • Nodal marginal zone lymphoma
  • Splenic marginal zone lymphoma
• Histologic transformation of indolent lymphomas to diffuse large B-cell lymphoma
• Mantle cell lymphoma
• Diffuse large B-cell lymphoma
• High-grade B-cell lymphomas (including high-grade B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 [double/triple hit lymphoma], high-grade B-cell lymphoma, not otherwise specified)
• Burkitt lymphoma
• HIV-related B-cell lymphomas
• Post-transplant lymphoproliferative disorders
• Castleman’s disease
• Hairy cell leukemia

1. engagement of immune effector cells,
2. by directly activating intracellular death signaling pathways and/or
3. activation of the complement cascade.

Per the prescribing information, obinutuzumab (Gazyva) is contraindicated in patients with known hypersensitivity reactions (e.g., anaphylaxis) to obinutuzumab or any of the excipients, including serum sickness with prior obinutuzumab use.

Per the prescribing information, obinutuzumab (Gazyva) carries the following warnings and precautions:

• Hepatitis B virus reactivation (black box warning)
• Progressive multifocal leukencephalopathy (black box warning)
• Infusion-related reactions
• Hypersensitvity reactions including serum sickness
• Tumor lysis syndrome
• Infections
• Neutropenia
• Thrombocytopenia
• Immunization
• Embryo-fetal toxicity.

Per the prescribing information, the most common adverse reactions (occurrence ≥ 20% and ≥ 2% greater in th Gazyva treated arm) were as follows:

• Previously untreated CLL: infusion-related reactions and neutropenia
• Relapsed or refractory NHL: infusion-related reactions, fatigue, neutropenia, cough, upper respiratory tract infections, and musculoskeletal pain
• Previously untreated NHL: infusion-related reactions, neutropenia, upper respiratory tract infections, cough, constipation, and diarrhea.

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).

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). 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).

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.

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.

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 (hazard ratio [HR] 0.33; 95% confidence interval [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.

B-Cell Lymphoma – Follicular Lymphoma Subtype

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.

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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 % 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.

On February 26, 2016, the U.S. FDA 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 (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.

B-Cell Lymphoma – Other Subtypes

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.

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.

Sehn and colleagues (2020) noted that rituximab (R) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is the current standard therapy for DLBCL. Obinutuzumab (G) has demonstrated activity and an acceptable safety profile when combined with CHOP (G-CHOP) in patients with advanced DLBCL. These researchers presented the final analysis of an open-label, phase-III clinical trial (the GOYA study), which compared the safety and efficacy of G-CHOP versus R-CHOP in patients with previously untreated DLBCL. Patients aged 18 years or older with previously untreated advanced DLBCL were randomly assigned to receive 8 21-day cycles of R or G, plus 6 or 8 cycles of CHOP. The primary end-point was investigator-assessed PFS; secondary end-points included OS, other time-to-event end-points, and safety; investigator-assessed PFS by cell of origin subgroup was an exploratory end-point. A total of 1,418 patients were randomized, with 1,414 included in this final analysis (G-CHOP, n = 704; R-CHOP, n = 710); 5-year PFS rates were 63.8 % and 62.6 % for G-CHOP and R-CHOP, respectively (stratified HR 0.94, 95 % CI: 0.78 to 1.12; p = 0.48). The results of the secondary efficacy end-points did not show a benefit of G-CHOP over R-CHOP. In the exploratory analysis, a trend towards benefit with G-CHOP over R-CHOP was apparent in the patients with germinal center B cell DLBCL. The safety profile of G-CHOP was as expected, and no new safety signals were observed. More grade 3 to 5 (75.1 % versus 65.8 %), serious (44.4 % versus 38.4 %), and fatal (6.1 % versus 4.4 %) AEs were observed in the G-CHOP arm compared with the R-CHOP arm, respectively, with the most common fatal AEs being infections. A higher incidence of late-onset neutropenia occurred in the G-CHOP arm (8.7 %) versus the R-CHOP arm (4.9 %). The authors concluded that the final analysis, similar to the primary analysis, did not show a PFS benefit of G-CHOP over R-CHOP in previously untreated patients with DLBCL. Moreover, these researchers stated that the results of the secondary end-points were consistent with the primary end-point; further exploratory analyses and investigation of biomarkers are ongoing to examine if there may be a role for obinutuzumab in identifiable subgroups of DLBCL.

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.

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.

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.

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.

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.

Hairy Cell Leukemia

Lupi and colleagues (2021) stated that experience with angiotensin-receptor neprilysin inhibitors (ARNI) in oncologic patients with heart failure (HF) is limited. These investigators reported a case of ARNI started as 1st-choice therapy in a patient with relapsing hairy cell leukemia (HCL) and HF with depressed left ventricular ejection fraction (LVEF). A middle-aged man, previously treated with rituximab for HCL, was scheduled for cardiologic screening before starting a new anti-neoplastic therapy for cancer relapse. The patient had symptomatic HF with reduced LVEF and high NT-proBNP levels. In this patient, early ARNI treatment was well-tolerated and produced a rapid and durable improvement of symptoms, LVEF and NT-proBNP levels. Consequently, the oncologic team could start an experimental treatment with obinutuzumab, with complete HCL remission. The authors concluded that in this patient with HCL and HF, ARNI therapy was safe and effective, contributing to un-delayed cancer treatment.

Nephrotic Syndrome

Dossier and colleagues (2021) noted that steroid-sensitive nephrotic syndrome (SSNS) is, in most patients, a chronic disease with 80 % experiencing at least 1 relapse after 1st flare. B-cell depletion using rituximab is effective in preventing relapse in steroid-dependent (SDNS) patients but fails to maintain long-term remission following B-cell recovery, possibly due to development of auto-reactive long-lived plasma cells. These investigators examined sequential combination of anti-CD20 antibody targeting all B-cell subsets, and anti-CD38 antibody with high plasma cell cytotoxicity in patients with uncontrolled SDNS after failure of 1 or several attempts at B-cell depletion. A total of 14 patients with median disease duration of 7.8 years received 1,000 mg/1.73 m2 obinutuzumab followed by 1,000 mg/1.73 m2 daratumumab 2 weeks later (OD sequence). Oral immunosuppression was discontinued within 6 weeks, and biological monitoring performed monthly until B-cell recovery. Median age at treatment was 11.0 [IQR 10.4 to 14.4] years. B-cell depletion was achieved in all patients, and B-cell reconstitution occurred in all at median 9.5 months following obinutuzumab injection. After median follow-up of 20.3 months (IQR 11.5 to 22.6), 5/14 patients relapsed including 4 within 100 days following B-cell repletion. Relapse-free survival (RFS) was 60 % at 24 months from obinutuzumab infusion. Mild infusion reactions were reported in 3/14 patients during obinutuzumab and 4/14 during daratumumab infusions. Mild transient neutropenia (500 to 1,000/mm3) occurred in 2/14 patients. Intravenous immunoglobulins (IVIGs) were administered to 12/14 patients due to hypogammaglobulinemia. Low IgA and IgM levels were noted in 8 and 14 patients, respectively. No severe infection was reported. The authors concluded that a combination of therapeutic monoclonal antibodies targeting the B-cell system and the production of antibodies might be effective to disrupt the chronic forms of idiopathic NS. However, a formal demonstration with a RCT comparing obinutuzumab alone versus the OD sequence is mandatory before expanding this strategy.

Waldenstrom Macroglobulinemia

Tomowiak and colleagues (2021) described the findings of a phase-II clinical trial that examined the combination of obinutuzumab and idelalisib in relapsed/refractory (R/R) Waldenstrom macroglobulinemia (WM). The objective was to determine the safety and efficacy of a fixed-duration chemotherapy-free treatment. During the induction phase, patients received obinutuzumab and idelalisib for 6 cycles, followed by a maintenance phase with idelalisib alone for less than or equal to 2 years. A total of 48 patients with R/R WM were treated with the induction combination, and 27 patients participated in the maintenance phase. The best responses, reached after a median of 6.5 months (inter-quartile range [IQR], 3.4 to 7.1; range of 2.6 to 22.1 months), were very good partial response (PR) in 5 patients, PR in 27 patients, and minor response in 3 patients, leading to ORR and major response rate (MRR) estimates of 71.4 % (95 % CI: 56.7 to 83.4) and 65.3 % (95 % CI: 50.4 to 78.3), respectively. With a median follow-up of 25.9 months, median PFS was 25.4 months (95 % CI: 15.7 to 29.0). Uni-variate analysis focusing on molecular screening found no significant impact of CXCR4 genotypes on responses and survivals but a deleterious impact of TP53 mutations on survival. Although there was no grade-5 toxicity, 26 patients were removed from the study because of side effects; the most frequent were neutropenia (9.4 %), diarrhea (8.6 %), and liver toxicity (9.3 %). The authors concluded that this phase-II clinical trial found interesting efficacy of the combination of obinutuzumab and idelalisib in symptomatic R/R WM patients, although toxicity was a major drawback. Moreover, these researchers stated that there is a need to develop new approaches in patients who are refractory to BTK inhibitors; this population may benefit from this therapeutic option, which could be examined in further clinical trials.

The authors stated that this study had several drawbacks; but suggested new treatment opportunities. First, with a median PFS of 25.5 months, these investigators reached the primary goal of demonstrating a median PFS of greater than or equal to 25 months compared with 15 months with usual therapy. Second, the sample size did not allow firm conclusions regarding the impact of genotype on efficacy, because the study was not designed for this endpoint. These findings suggested that this combination might be of interest in CXCR4MUT WM patients with advanced disease, because they demonstrated reduced response to ibrutinib. Compensatory PI3K/Akt signaling may contribute to ibrutinib resistance in the CXCR4MUT WM model, as well as in the CXCR4WT WM model, resulting in synthetic lethality toward the PI3K/Akt inhibitor. Thus, targeting of the PI3K/Akt pathway could be an option in BTK inhibitor-resistant WM patients and appeared to be a proof-of-concept regarding the efficacy of this class of compound in WM patients. Furthermore, for the 1st time, these researchers provided an estimate of the response rate or PFS achieved with a combination regimen including inhibitors of BCR-associated kinases in TP53MUT WM patients; however, the number of patients was small, and a non-statistically significant deleterious effect of TP53 mutation was observed. Third, the safety of the combination with high liver and gastro-intestinal (GI) toxicity led to early treatment discontinuation and/or a dose reduction in 50 % of the patients. Using Bayesian analysis, which quantified, via probabilistic statements, the proportion of treated patients who experienced grade-3 or garde-4 AEs, it appeared more than likely (98 %) that more than 75 % of patients could be impacted by such events. It was a limitation of further clinical use. However, considering the potential efficacy of this class of agents, next-generation PI3K inhibitors associated with obinutuzumab could overcome the toxicity profile observed in this phase-II clinical trial and may be a reasonable therapeutic option when standard therapies have been exhausted.

Immune Thrombotic Thrombocytopenic Purpura

Doyle et al (2022) stated that rituximab can be used to treat immune thrombotic thrombocytopenic purpura (iTTP) during acute presentation or disease relapse. Side-effects include severe hypersensitivity reactions, especially anaphylaxis and rituximab-induced serum sickness, with a minority not maintaining a response to treatment. Alternative humanized anti-CD20 treatments, obinutuzumab and ofatumumab, have been used. A review of the United Kingdom TTP Registry showed 15 patients received these drugs over 26 treatment episodes (8 obinutuzumab and 18 ofatumumab). Indications for alternative anti-CD20 treatment were severe infusion-related reactions, acute rituximab-induced serum sickness and a short duration of disease remission. All patients achieved disease remission (ADAMTS13 [A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13] activity of 30 iu/dL or higher) after a median 15 days and 92 % of episodes achieved complete remission (CR; 60 iu/dL or higher). A total of 7 patients required further treatment for disease relapse with a median RFS of 17.4 months. All patients continued to respond to re-treatment with the preceding drug when relapse occurred. There were 4 AEs in 26 treatment episodes (15 %) – 2 infections and 2 infusion reactions. The authors concluded that the findings of this study suggested that obinutuzumab and ofatumumab may be considered as an alternative option to rituximab in the treatment of iTTP with a comparable safety profile, absence of significant hypersensitivity reactions and sustained normalization of ADAMTS13.

Lupus Nephritis

In a systematic review and meta-analysis, Chen et al (2022) examined the safety and effectiveness of biological agents for the treatment of lupus nephritis (LN). PubMed, Embase, and the Cochrane Library databases were searched from their inception up to November 2021. The outcomes were overall response, CR, proteinuria, renal activity index, and AEs. Only RCTs were included. A total of 9 RCTs (1,645 patients) were included. The RCTs evaluated abatacept (n = 2), belimumab (n = 1), obinutuzumab (n = 1), atacicept (n = 1), IL-2 (n = 1), ocrelizumab (n = 1), and rituximab (n = 2). The use of biological agents was associated with higher likelihoods of achieving an overall response (relative risk [RR], 1.26; 95 % CI: 1.15 to 1.39; p < 0.001; I2 = 14.3 %; pQ = 0.301) and a CR (RR, 1.33; 95 % CI: 1.16 to 1.54; p < 0.001; I2 = 41.8 %; pQ = 0.056). The use of biological agents was not associated with improvements in the urinary protein-to-creatinine ratio (weighted mean difference [WMD], 3.83; 95 % CI: -3.71 to 11.38; p = 0.319; I2 = 99.4 %; pQ < 0.001). The use of biological agents in patients with LN was also not associated with an increased risk of any AEs (RR, 1.01; 95 % CI: 0.98 to 1.04; p = 0.519; I2 = 0.0 %; pQ = 0.533), serious AEs (RR, 0.95; 95 % CI: 0.82 to 1.09; p = 0.457; I2 = 0.0 %; pQ = 0.667), grade greater than 3 AEs (RR, 0.91; 95 % CI: 0.67 to 1.22; p = 0.522; I2 = 0.0 %; pQ = 0.977), infections (RR, 1.09; 95 % CI: 0.99 to 1.20; p = 0.084; I2 = 0.0 %; pQ = 0.430), and deaths (RR, 0.67; 95 % CI: 0.36 to 1.24; p = 0.200; I2 = 0.0 %; pQ = 0.439). The meta-regression analysis showed that follow-up duration and the sample size did not influence the CR rate, whereas publications in 2012 to 2014 influence the rate compared with 2015 to 2020. The authors concluded that biological agents appeared to be safe and effective for managing patients with LN.

These investigators noted that LN occurs in approximately 40 % of SLE patients, mostly within 5 years from the SLE diagnosis, and presents a rate of progression to end-stage renal disease of 4.3 % to 10.1 %. Patients with LN have a poorer prognosis than patients with SLE without kidney involvement, reported at 5 % to 25 % at 5 years. Still, there is uncertainty regarding the safety and effectiveness of biological agents for LN. A RCT confirmed that, although rituximab therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels, it did not improve clinical outcomes after 1 year of treatment. The combination of rituximab with mycophenolate mofetil and corticosteroids did not result in any new or unexpected safety signals. Another controlled trial confirmed that, in patients with active LN, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone. These researchers stated that given the conflicting results, a higher level of evidence was needed.

Combined Obinutuzumab and Pixantrone for Relapsed Aggressive Lymphoma

Hess et al (2022) stated that the prognosis of patients with relapsed DLBCL remains poor with current options. In a phase-II clinical trial, these researchers examined combined obinutuzumab and pixantrone for up to 6 cycles for patients with relapsed or refractory DLBCL. Overall response rate (ORR) was the primary endpoint. A total of 68 patients were evaluated, median age was 75 years, median number of prior lines was 3 (range of 1 to 10), 52 patients (76.5 %) were diagnosed with DLBCL and 16 (23.5 %) patients had transformed indolent lymphoma or FL IIIB. ORR was 35.3 % for all and 40 % for evaluable patients (16.6 % CR), median PFS and OS were 2.8 months and 8 months, respectively. Analysis of the cell of origin revealed a superior course for patients with non-GCB (germinal center B-cell-like) phenotype [median OS not reached (n.r.) versus 5.2 months]. Patients with 1 prior line had an improved outcome over patients treated in later lines (PFS n.r. versus 2.5 months). Disease progression was the main reason for premature termination; AEs were mainly hematologic. The combination treatment revealed no unexpected AEs. Most relevant non-hematologic toxicity was infection in 28 % of patients. The authors concluded that combined Obinutuzumab and pixantrone showed clinical activity with sometimes long-term remission; however, the trial failed to meet its primary endpoint. These researchers stated that further investigations are needed to define a role in the increasingly complex algorithm.

References

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