Medical Policy

Policy Num:       05.001.044
Policy Name:     Polivy® (polatuzumab vedotin-piiq)
Policy ID:          [05.001.044] [Ac / L / M+ / P+] [0.00.00]

Last Review:       September 25, 2025
Next Review:      September 20, 2026
 

Related Policies: None

 Polivy^® (polatuzumab vedotin-piiq)

Summary

Polivy® (polatuzumab vedotin-piiq) is an antibody-drug conjugate directed against CD79b. It is FDA-approved in combination regimens for adult patients with diffuse large B-cell lymphoma (DLBCL)

Objective

The objective to define medical necessity criteria for Polivy in accordance with FDA labeling, NCCN guidelines, and current standards of care, ensuring appropriate utilization and patient safety.

Policy Statements

Polatuzumab vedotin-piiq (Polivy) is considered medically necessary when ALL the following criteria are met:
 
1. FDA-Approved Indications
 
First-line therapy for diffuse large B-cell lymphoma, in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP).
 
Relapsed or refractory diffuse large B-cell lymphoma after two or more prior lines of therapy, in combination with bendamustine and rituximab (Pola-BR).

2. Off-Label Uses Supported by NCCN (Category 1 or 2A)
 
Follicular lymphoma (Grade 1–2).
 
Mantle cell lymphoma.
 
High-grade B-cell lymphomas.
 
Human immunodeficiency virus (HIV)-related B-cell lymphomas.
 
Post-transplant lymphoproliferative disorder.
 
Bridging therapy prior to chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory disease.

3. Clinical Documentation Requirements
 
Pathology confirming CD20-positive B-cell lymphoma.
 
Performance status and treatment intent documented.
 
Exclusion of investigational agents unless supported by NCCN or CMS guidance.

Policy Guidelines

Dosing and administration must follow FDA prescribing information.
 
Monitor for cytopenias, neuropathy, infections, hepatotoxicity, and infusion-related reactions.
 
Prior authorization requires clinical documentation of diagnosis, prior therapies, and rationale for therapy selection.
 

Benefit Application

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Prior authorization is required.

Background

U.S. Food and Drug Administration (FDA)-Approved Indications
Polivy in combination with bendamustine and a rituximab product is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, after at least two prior therapies.
Polivy in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of adult patients who have previously untreated diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) or high-grade B-cell lymphoma (HGBL) and who have an International Prognostic Index score of 2 or greater.
Compendial Uses
B-Cell Lymphomas
Human immunodeficiency virus (HIV)-related B-cell lymphomas (HIV-related diffuse large B-cell lymphoma, primary effusion lymphoma, HIV-related plasmablastic lymphoma, and human herpesvirus-8 (HHV8)-positive diffuse large B-cell lymphoma)
Diffuse large B-cell lymphoma (DLBCL)
High-grade B-cell lymphomas (HGBLs)
Histologic transformation of indolent lymphomas to diffuse large B-cell lymphoma
Histological transformation of indolent lymphomas to high-grade B-cell lymphoma with MYC and BCL6 without BCL2 rearrangements
Monomorphic post-transplant lymphoproliferative disorders (B-cell type)
Polatuzumab vedotin-piiq is available as Polivy (Genentech, Inc.). Polatuzumab vedotin-piiq is an antibody that is attached to a chemotherapy drug (antibody-drug conjugate). Polatuzumab binds to the CD79b protein found only on B cells, then releases the chemotherapy drug into those cells.

Per the prescribing information, polatuzumab vedotin-piiq (Polivy) carries the following warnings and precautions:

Peripheral neuropathy: In Study GO29365, 40% (69/173) patients treated with Polivy experienced new or worsening peripheral neuropathy. The peripheral neuropathy was Grade 1 in 26% of cases, Grade 2 in 12%, and Grade 3 in 2.3%.
Infusion-related reactions: In Study GO29365, reported infusion-related reactions following Polivy administration were Grade 1 in 67%, Grade 2 in 25%, and Grade 3 in 8% of patients.
Myelosuppression: In patients treated with Polivy, Grade 3 or higher hematologic adverse reactions included neutropenia (42%), thrombocytopenia (40%), anemia (24%), lymphopenia (13%), and febrile neutropenia (11%).
Serious and opportunistic infections: In patients treated with Polivy, Grade 3 or higher infections occurred in 32% (55/173) of patients.
Progressive multifocal leukoencephalopathy (PML); Following treatment with Polivy, PML was reported in 0.6% (1/173) patients.
Tumor lysis syndrome
Hepatotoxicity: In Study GO29635, Grade 3 and 4 transaminase elevations occurred in 1.9% and 1.9% of patients, respectively
Embryo-fetal toxicity.
The most common adverse reactions (≥20%) noted were neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia (Genentech, 2020).

On June 10, 2019, The U.S. Food and Drug Administration (FDA) approved Polivy (polatuzumab vedotin-piiq), in combination with the chemotherapy bendamustine and a rituximab product (a combination known as “BR”), to treat adult patients with diffuse large B-cell lymphoma (DLBCL) that has progressed or returned after at least two prior therapies. Polatuzumab is a novel antibody-drug conjugate intended to target specific cells (FDA, 2019).Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL) accounting for approximately 25 percent of NHL cases. In the United States and England, the incidence of DLBCL is approximately 7 cases per 100,000 persons per year and the incidence varies by ethnicity, with Caucasian Americans having higher rates than Blacks, Asians, and American Indian or Alaska Natives, in order of decreasing incidence. Like most other NHLs, there is a male predominance with approximately 55 percent of cases occurring in men. Incidence increases with age; the median age at presentation is 64 years for patients, with a younger age for Blacks than for Caucasian Americans. Although it can be cured, about 30 to 40% of patients suffer relapse. This type of cancer grows quickly in the lymph nodes and may affect the bone marrow, spleen, liver or other organs. Signs and symptoms of DLBCL may include swollen lymph nodes, fever, recurring night sweats and weight loss (Freedman and Aster, 2023; FDA, 2019).

The efficacy of polatuzumab was evaluated in Study GO29365 (NCT02257567), an open-label, multicenter clinical trial that included a cohort of 80 patients with relapsed or refractory DLBCL after least one prior regimen. Patients were randomized 1:1 to receive either polatuzumab in combination with bendamustine and a rituximab product (BR) or BR alone for six 21-day cycles. Randomization was stratified by duration of response (DOR) to last therapy. Eligible patients were not candidates for autologous HSCT at study entry. The study excluded patients with Grade 2 or higher peripheral neuropathy, prior allogeneic HSCT, active central nervous system lymphoma, or transformed lymphoma. Following premedication with an antihistamine and antipyretic, polatuzumab was given by intravenous infusion at 1.8 mg/kg on Day 2 of Cycle 1 and on Day 1 of Cycles 2–6. Bendamustine was administered at 90 mg/m2 intravenously daily on Days 2 and 3 of Cycle 1 and on Days 1 and 2 of Cycles 2–6. A rituximab product was administered at a dose of 375 mg/m2 intravenously on Day 1 of Cycles 1–6. The cycle length was 21 days. Of the 80 patients randomized to receive polatuzumab plus BR (n = 40) or BR alone (n = 40), the median age was 69 years (range: 30–86 years), 66% were male, and 71% were white. Most patients (98%) had DLBCL not otherwise specified. The primary reasons patients were not candidates for HSCT included age (40%), insufficient response to salvage therapy (26%), and prior transplant failure (20%). The median number of prior therapies was 2 (range: 1–7), with 29% receiving one prior therapy, 25% receiving 2 prior therapies, and 46% receiving 3 or more prior therapies. Eighty percent of patients had refractory disease to last therapy. In the polatuzumab plus BR arm, patients received a median of 5 cycles, with 49% receiving 6 cycles. In the BR arm, patients received a median of 3 cycles, with 23% receiving 6 cycles (Genentech, 2019). Efficacy was based on complete response (CR) rate at the end of treatment and DOR, as determined by an independent review committee (IRC). End of treatment was defined as 6–8 weeks after Day 1 of Cycle 6 or last study treatment. In the polatuzumab group, 16 (40%) patients experienced complete response compared with 7 (18%) patients in the BR group, 95% CI: 22 (3, 41). In the polatuzumab arm, of the 25 patients who achieved a partial or complete response, 16 (64%) had a DOR of at least 6 months, and 12 (48%) had a DOR of at least 12 months. In the BR arm, of the 10 patients who achieved a partial or complete response, 3 (30%) had a DOR lasting at least 6 months, and 2 (20%) had a DOR lasting at least 12 months. Other efficacy measures included IRC- assessed best overall response. In the polatuzumab group, 25 (63%) patients experienced best response overall response of complete response or partial remission, compared with 10 (25%) patients in the BR group. Objective response at the end of treatment occurred in 18 (45%) of patients in the polatuzumab group, and in 7 (18%) of patients in the BR group (Genentech, 2019).

On April 19, 2023, the U.S. Food and Drug Administration (FDA) expanded the approval for polatuzumab vedotin-piiq (Polivy) to include treatment of adult patients who have previously untreated diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) or high-grade B-cell lymphoma (HGBL) and who have an International Prognostic Index score of 2 or greater, in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP). The FDA approval for this expanded indication was based on supporting data from the POLARIX study (FDA, 2023).

In the POLARIX study, a randomized, double-blind, placebo-controlled trial, investigators evaluated the efficacy of Polivy in patients with previously untreated large B-cell lymphoma and an International Prognostic Index score of 2-5. The trial assessed superiority of switching Polivy for vincristine in the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone regimen. Randomization was 1:1 for patients receiving either Polivy plus rituximab, cyclophosphamide, doxorubicin, and prednisone or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for six 21-day cycles, followed by two additional cycles of rituximab alone in both arms. The main diagnoses were de novo diffuse large B-cell lymphoma, not otherwise specified and high-grade B-cell lymphoma. Efficacy was determined from investigator-assessed progression-free survival. The experimental arm showed a statistically significantly longer progression-free survival with a hazard ratio of 0.73. This arm also showed a statistically significant improvement in modified event-free survival. Furthermore, no significant difference in complete response rate or overall survival was noted (FDA, 2023).

B-Cell Lymphomas
Tilly et al (2019; NCT01992653) stated polatuzumab vedotin, an antibody-drug conjugate targeting the CD79b component of the B-cell receptor, has demonstrated activity as a single agent and in combination with rituximab in relapsed or refractory diffuse large B-cell lymphoma. In this study, the authors evaluated the safety and preliminary activity of polatuzumab vedotin in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, and prednisone (CHP) in patients with previously untreated diffuse large B-cell lymphoma. This was an open-label, non-randomized study composed of a phase 1b dose escalation and a phase 2 dose expansion at 11 hospitals and health centers in the USA and France. Patients aged 18 years or older with B-cell non-Hodgkin lymphoma were eligible. Exclusion criteria included peripheral neuropathy with grade greater than 1, major surgery within 4 weeks before enrolment, known CNS involvement of lymphoma, and uncontrolled heart disease. Phase 1b dose escalation had a three-plus-three design and established the recommended phase 2 dose. Phase 2 expansion evaluated the recommended phase 2 dose of polatuzumab vedotin in patients with newly diagnosed diffuse large B-cell lymphoma with an International Prognostic Index (IPI) of 2-5. Patients received cyclophosphamide 750 mg/m2 on day 1 intravenously, doxorubicin 50 mg/m2 on day 1 intravenously, and prednisone 100 mg once daily on days 1-5 of each 21-day cycle orally (CHP), plus either rituximab 375 mg/m2 intravenously on day 1 of each cycle (R-CHP) or obinutuzumab 1000 mg intravenously on days 1, 8, and 15 of cycle 1 and on day 1 of the following cycles (G-CHP). Polatuzumab vedotin was administered on day 2 of cycles 1 and 2, and on day 1 of the following cycles at 1·0-2·4 mg/kg during the escalation phase and at the recommended phase 2 dose during the expansion phase. Treatment could last six or eight cycles, depending on investigator preference. The primary endpoints of the study were safety and tolerability, and determination of the maximum tolerated dose (or recommended phase 2 dose) of polatuzumab vedotin. All endpoints were analyzed per protocol in the safety evaluable population, defined as all patients who received at least one dose of study treatment. Between Dec 4, 2013, and July 26, 2016, 85 patients were enrolled. 82 patients were included in the safety and activity evaluable populations, 25 in phase 1b and 57 in phase 2. In light of information from other studies using polatuzumab vedotin reported during this study, in which the safety profile associated with exposure to polatuzumab vedotin at doses higher than 1·8 mg/kg every 3 weeks was not outweighed by any clinical benefit, the recommended phase 2 dose was set to 1·8 mg/kg in the R-CHP cohort and no higher doses were explored in this study. 66 patients with newly diagnosed diffuse large B-cell lymphoma received the polatuzumab vedotin recommended phase 2 dose (45 R-CHP; 21 G-CHP). In 66 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose, the most common adverse events of grade 3 or worse were neutropenia (20 [30%]), febrile neutropenia (12 [18%]), and thrombocytopenia (six [9%]). Among the 70 patients (any histology) who received the recommended phase 2 dose, 19 (27%) had grade 1 peripheral neuropathy, eight (11%) grade 2, and two (3%) grade 3. Four deaths were reported during follow-up: two treatment-related (one complication of atrial fibrillation and one septic shock) and two deaths were due to disease progression. As of the cutoff date of Dec 29, 2017, median follow-up time was 21·5 months (IQR 16·7-24·3) for the untreated diffuse large B-cell lymphoma cohort treated at the polatuzumab vedotin recommended phase 2 dose. 59 (89%) patients achieved an overall response at end of treatment (51 [77%] patients had a complete response, and eight [12%] patients had a partial response). The safety of incorporating polatuzumab vedotin to R-CHP or G-CHP was as expected and manageable. Preliminary clinical activity in newly diagnosed diffuse large B-cell lymphoma seems promising and encouraged a phase 3 trial comparing polatuzumab vedotin with R-CHP to R-CHOP (Tilly et al, 2019).

Morschhauser et al (2019; NCT01691898) stated antibody-drug conjugates (ADCs) polatuzumab vedotin (pola) and pinatuzumab vedotin (pina) showed clinical activity and tolerability in phase 1 trials. The aim of this multicenter, open-label, phase 2 study was to compare rituximab plus pola (R-pola) or pina (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. In this phase 2 randomized study at 39 investigational sites in six countries, patients were randomly assigned (1:1), by use of a dynamic hierarchical randomization scheme, to receive R-pola or R-pina (375 mg/m2 rituximab plus 2·4 mg/kg ADCs) every 21 days until disease progression or unacceptable toxicity up to 1 year. Treatment allocations were not masked to the investigator, patients or sponsor after the patients were enrolled and randomly assigned. The primary objectives were safety and tolerability, and antitumor response. The study is closed to accrual. 81 patients with diffuse large B-cell lymphoma and 42 with follicular lymphoma were recruited between Sept 27, 2012, and Oct 10, 2013, and were assigned to treatment. 81 patients with diffuse large B-cell lymphoma and 41 patients with follicular lymphoma were eligible for analysis. Of the 42 patients with diffuse large B-cell lymphoma who received R-pina, 25 (60%, 95% CI: 43-74) achieved an objective response and 11 (26%, 95% CI: 14-42) achieved a complete response. Of the 39 patients in this cohort who received R-pola, 21 (54%, 95% CI: 37-70) achieved an objective response, and eight (21%, 95% CI: 9-36) achieved a complete response. Of the 21 patients in the follicular lymphoma cohort who received R-pina, 13 (62%, 95% CI: 38-82) achieved an objective response, and one (5%, 95% CI: 0·1-24) achieved a complete response. Of the 20 patients in this cohort who received R-pola, 14 (70%, 95% CI: 46-88) achieved an objective response, and nine (45%, 95% CI: 23-68) achieved a complete response. In the diffuse large B-cell lymphoma cohort, grade 3-5 adverse events occurred in 33 (79%) of 42 patients receiving R-pina (most common were neutropenia [29%] and hyperglycemia [10%]; nine [21%] grade 5 adverse events, five of which were infection-related), and in 30 (77%) of 39 patients receiving R-pola (most common were neutropenia [23%], anemia [8%] and diarrhea [8%]; no grade 5 adverse events). In the follicular lymphoma cohort, grade 3-5 adverse events occurred in 13 (62%) of 21 patients receiving R-pina (most common were neutropenia [29%] and hyperglycemia [14%]; no grade 5 adverse events) and in ten (50%) of 20 patients receiving R-pola (most common were neutropenia [15%] and diarrhea [10%]; one grade 5 adverse event). The authors concluded that R-pina and R-pola are potential treatment options in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. Pola was selected by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response than pina, and an overall benefit-risk favoring R-pola (Morschhauser et al, 2019).

Davis et al (2023) stated that DLBCL is the most common type of aggressive NHL in the U.S.  For nearly 20 years, standard front-line treatment has consisted of chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).  Numerous trials have unsuccessfully attempted to achieve better outcomes in these patients.  Recently, the results of the phase-III clinical study (the POLARIX Trial) were published.  This trial randomized newly diagnosed DLBCL patients to receive polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) or standard-of-care (SOC) R-CHOP.  The POLARIX Trial reported 2-year PFS of 76.7 % for pola-R-CHP compared with 70.2 % for R-CHOP with comparable safety profiles between the 2 arms.  Based on these findings, a new SOC may be emerging in patients with DLBCL.  The authors concluded that polatuzumab vedotin in combination with R-CHP provided a new therapeutic option for patients with newly diagnosed DLBCL.  Patients over 60 years of age with IPI scores of 3 to 5, non-bulky disease, and non-germinal center B-cell (GCB) subtype may benefit more with pola-R-CHP over R-CHOP.  Significant differences observed in PFS may be substantial enough for some clinicians to begin incorporating pola-R-CHP into their therapeutic approach of newly diagnosed DLBCL.  Continued follow-up and further data maturation may elucidate a difference in OS.  A cost-benefit comparison between the 2 arms should also be considered to examine if the higher upfront costs of pola-R-CHP would translate into cost avoidance of subsequent therapy.  Due to the positive results with polatuzumab vedotin in the front-line and R/R, there are ongoing studies examining its use in combination with other therapies.

Burkitt Lymphoma
Alanzi et al (2023) noted that although Burkitt lymphoma (BL) is considered a curable disease due to the progress made in choosing the most effective 1st-line therapy, relapsed or refractory (R/R) BL has a very poor outcome.  There is a lack of data supporting the therapeutic regimens.  These investigators reported on the findings of a 48-year-old man with stage-II BL with no response to the 1st-line of high-intensity chemotherapy.  However, treatment with polatuzumab vedotin resulted in complete clinical remission for more than 1 year.  The authors reported the 1st use of polatuzumab vedotin in R/R BL with an appropriate response.  Moreover, these researchers stated that further investigation is needed to ascertain its effectiveness and adverse effects.

Polatuzumab, Rituximab, and Bendamustine Combination in Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Dal et al (2023) stated that polatuzumab vedotin (Pola) with bendamustine and rituximab (BR) is a promising option for patients with R/R DLBCL.  In a retrospective study, these researchers examined the data of 71 R/R DLBCL patients who had been treated with Pola-BR in the named patient program from March 2018 to April 2021 from 32 centers in Turkey.  All patients received up to 6 cycles of Pola 1.8 mg/kg, rituximab 375 mg/m2 on day 1, and bendamustine 90 mg/m2 on days 1 to 2 of each cycle.  Median age at Pola-BR initiation was 55 (19 to 84) years.  The ORR was 47.9 %, including 32.4 % CR rate when a median of 3 cycles was employed.  With a median follow-up of 5 months, the median OS was 5 months.  Grade-III to grade-IV neutropenia and thrombocytopenia were the most common hematological toxicities.  The authors concluded that the real-world data from this cohort of hard-to-treat and aggressive R/R DLBCL showed that the Pola-BR combination is a promising entrant to the R/R DLBCL treatment landscape with a manageable toxicity profile.  Moreover, these researchers stated that further studies are needed to improve the identification of patients who will likely benefit from polatuzumab vedotin treatment.

The authors stated that this study had several drawbacks including the absence of a comparison group and the retrospective design, where these investigators depended mainly on medical records for data collection.  Side effects were also collected retrospectively from medical records.  The follow-up period was limited since their sample consisted of a group of high-risk patients who had exhausted all available therapeutic options.  Most of the recruited patients had adverse prognostic factors including the presence of advanced stage, high IPI score, bulky disease, and the requirement of multiple previous lines of treatment.  Another important point which may explain the short follow-up duration was the fact that 1/3 of included patients had ECOG PS scores of 2 to 4.  In the follow-up period, 55 (77.5 %) patients died from their disease who received only median 3 cycles of Pola-BR.

Regulatory Status

FDA Approvals:
 
2019 – Pola-BR for R/R DLBCL after ≥ 2 prior therapies.
 
2023 – Pola-R-CHP for previously untreated DLBCL/HGBL with IPI ≥ 2.
 

Rationale

Polivy® (polatuzumab vedotin-piiq) has demonstrated clinical benefit in multiple randomized controlled trials and real-world evidence:
 
GO29365 Trial: This phase 1b/2 study established the efficacy of Polivy (polatuzumab vedotin-piiq) in combination with bendamustine and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma, showing improved progression-free survival and overall survival compared to bendamustine with rituximab alone.
 
POLARIX Trial (NEJM 2022): Demonstrated that Polivy (polatuzumab vedotin-piiq) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone improved progression-free survival compared to the standard regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma. This evidence led to the 2023 FDA approval for frontline use.
 
NCCN Guidelines v.2025: Endorse Polivy-based regimens as Category 1 for diffuse large B-cell lymphoma (both first-line and relapsed/refractory) and Category 2A for multiple additional B-cell lymphoma subtypes, including follicular lymphoma, mantle cell lymphoma, HIV-related B-cell lymphoma, and post-transplant lymphoproliferative disorder.
 
Safety data: Risks include peripheral neuropathy, cytopenias, and infections, which are manageable with monitoring and supportive care.
 
The clinical benefit is most significant in patients not eligible for stem cell transplant or CAR T-cell therapy. However, Polivy is also recognized as an effective bridging therapy to CAR T-cell therapy.
 
Conclusion: The evidence supports that Polivy (polatuzumab vedotin-piiq), when used in combination with standard chemotherapy backbones such as bendamustine with rituximab or rituximab with cyclophosphamide, doxorubicin, and prednisone, provides clinically meaningful improvements in survival and health outcomes. This justifies its coverage under medical necessity when used per FDA label or NCCN Compendia.

Relapsed or Refractory Diffuse Large B-cell Lymphoma

The efficacy of POLIVY was evaluated in Study GO29365 (NCT02257567), an open-label, multicenter clinical trial that included a cohort of 80 patients with relapsed or refractory DLBCL after least one prior regimen. Patients were randomized 1:1 to receive either POLIVY in combination with bendamustine and a rituximab product (BR) or BR alone for six 21-day cycles. Randomization was stratified by duration of response (DOR) to last therapy. Eligible patients were not candidates for autologous HSCT at study entry. The study excluded patients with Grade 2 or higher peripheral neuropathy, prior allogeneic HSCT, active central nervous system lymphoma, or transformed lymphoma.

Following premedication with an antihistamine and antipyretic, POLIVY was given by intravenous infusion at 1.8 mg/kg on Day 2 of Cycle 1 and on Day 1 of Cycles 2–6.

Bendamustine was administered at 90 mg/m2 intravenously daily on Days 2 and 3 of Cycle 1 and on Days 1 and 2 of Cycles 2–6. A rituximab product was administered at a dose of 375 mg/m2 intravenously on Day 1 of Cycles 1–6. The cycle length was 21 days. Of the 80 patients randomized to receive POLIVY plus BR (n = 40) or BR alone (n = 40), the median age was 69 years (range: 30–86 years), 66% were male, and 71% were white. Most patients (98%) had DLBCL not otherwise specified. The primary reasons patients were not candidates for HSCT included age (40%), insufficient response to salvage therapy (26%), and prior transplant failure (20%). The median number of prior therapies was 2 (range: 1–7), with 29% receiving one prior therapy, 25% receiving 2 prior therapies, and 46% receiving 3 or more prior therapies. Eighty percent of patients had refractory disease to last therapy.

In the POLIVY plus BR arm, patients received a median of 5 cycles, with 49% receiving 6 cycles. In the BR arm, patients received a median of 3 cycles, with 23% receiving 6 cycles. Efficacy was based on complete response (CR) rate at the end of treatment and DOR, as determined by an independent review committee (IRC). Other efficacy measures included IRCassessed best overall response.

In the POLIVY plus BR arm, of the 25 patients who achieved a partial or complete response, 16 (64%) had  a DOR of at least 6 months, and 12 (48%) had a DOR of at least 12 months. In the BR arm, of the 10 patients who achieved a partial or complete response, 3 (30%) had a DOR lasting at least 6 months, and 2 (20%) had a DOR lasting at least 12 months.

Tilly et al (2019; NCT01992653) stated polatuzumab vedotin, an antibody-drug conjugate targeting the CD79b component of the B-cell receptor, has demonstrated activity as a single agent and in combination with rituximab in relapsed or refractory diffuse large B-cell lymphoma. In this study, the authors evaluated the safety and preliminary activity of polatuzumab vedotin in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, and prednisone (CHP) in patients with previously untreated diffuse large B-cell lymphoma. This was an open-label, non-randomized study composed of a phase 1b dose escalation and a phase 2 dose expansion at 11 hospitals and health centers in the USA and France. Patients aged 18 years or older with B-cell non-Hodgkin lymphoma were eligible. Exclusion criteria included peripheral neuropathy with grade greater than 1, major surgery within 4 weeks before enrolment, known CNS involvement of lymphoma, and uncontrolled heart disease. Phase 1b dose escalation had a three-plus-three design and established the recommended phase 2 dose. Phase 2 expansion evaluated the recommended phase 2 dose of polatuzumab vedotin in patients with newly diagnosed diffuse large B-cell lymphoma with an International Prognostic Index (IPI) of 2-5. Patients received cyclophosphamide 750 mg/m2 on day 1 intravenously, doxorubicin 50 mg/m2 on day 1 intravenously, and prednisone 100 mg once daily on days 1-5 of each 21-day cycle orally (CHP), plus either rituximab 375 mg/m2 intravenously on day 1 of each cycle (R-CHP) or obinutuzumab 1000 mg intravenously on days 1, 8, and 15 of cycle 1 and on day 1 of the following cycles (G-CHP). Polatuzumab vedotin was administered on day 2 of cycles 1 and 2, and on day 1 of the following cycles at 1·0-2·4 mg/kg during the escalation phase and at the recommended phase 2 dose during the expansion phase. Treatment could last six or eight cycles, depending on investigator preference. The primary endpoints of the study were safety and tolerability, and determination of the maximum tolerated dose (or recommended phase 2 dose) of polatuzumab vedotin. All endpoints were analyzed per protocol in the safety evaluable population, defined as all patients who received at least one dose of study treatment. Between Dec 4, 2013, and July 26, 2016, 85 patients were enrolled. 82 patients were included in the safety and activity evaluable populations, 25 in phase 1b and 57 in phase 2. In light of information from other studies using polatuzumab vedotin reported during this study, in which the safety profile associated with exposure to polatuzumab vedotin at doses higher than 1·8 mg/kg every 3 weeks was not outweighed by any clinical benefit, the recommended phase 2 dose was set to 1·8 mg/kg in the R-CHP cohort and no higher doses were explored in this study. 66 patients with newly diagnosed diffuse large B-cell lymphoma received the polatuzumab vedotin recommended phase 2 dose (45 R-CHP; 21 G-CHP). In 66 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose, the most common adverse events of grade 3 or worse were neutropenia (20 [30%]), febrile neutropenia (12 [18%]), and thrombocytopenia (six [9%]). Among the 70 patients (any histology) who received the recommended phase 2 dose, 19 (27%) had grade 1 peripheral neuropathy, eight (11%) grade 2, and two (3%) grade 3. Four deaths were reported during follow-up: two treatment-related (one complication of atrial fibrillation and one septic shock) and two deaths were due to disease progression. As of the cutoff date of Dec 29, 2017, median follow-up time was 21·5 months (IQR 16·7-24·3) for the untreated diffuse large B-cell lymphoma cohort treated at the polatuzumab vedotin recommended phase 2 dose. 59 (89%) patients achieved an overall response at end of treatment (51 [77%] patients had a complete response, and eight [12%] patients had a partial response). The safety of incorporating polatuzumab vedotin to R-CHP or G-CHP was as expected and manageable. Preliminary clinical activity in newly diagnosed diffuse large B-cell lymphoma seems promising and encouraged a phase 3 trial comparing polatuzumab vedotin with R-CHP to R-CHOP (Tilly, 2019).

Morschhauser et al (2019; NCT01691898) stated antibody-drug conjugates (ADCs) polatuzumab vedotin (pola) and pinatuzumab vedotin (pina) showed clinical activity and tolerability in phase 1 trials. The aim of this multicenter, open-label, phase 2 study was to compare rituximab plus pola (R-pola) or pina (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. In this phase 2 randomized study at 39 investigational sites in six countries, patients were randomly assigned (1:1), by use of a dynamic hierarchical randomization scheme, to receive R-pola or R-pina (375 mg/m2 rituximab plus 2·4 mg/kg ADCs) every 21 days until disease progression or unacceptable toxicity up to 1 year. Treatment allocations were not masked to the investigator, patients or sponsor after the patients were enrolled and randomly assigned. The primary objectives were safety and tolerability, and antitumor response. The study is closed to accrual. 81 patients with diffuse large B-cell lymphoma and 42 with follicular lymphoma were recruited between Sept 27, 2012, and Oct 10, 2013, and were assigned to treatment. 81 patients with diffuse large B-cell lymphoma and 41 patients with follicular lymphoma were eligible for analysis. Of the 42 patients with diffuse large B-cell lymphoma who received R-pina, 25 (60%, 95% CI: 43-74) achieved an objective response and 11 (26%, 95% CI: 14-42) achieved a complete response. Of the 39 patients in this cohort who received R-pola, 21 (54%, 95% CI: 37-70) achieved an objective response, and eight (21%, 95% CI: 9-36) achieved a complete response. Of the 21 patients in the follicular lymphoma cohort who received R-pina, 13 (62%, 95% CI: 38-82) achieved an objective response, and one (5%, 95% CI: 0·1-24) achieved a complete response. Of the 20 patients in this cohort who received R-pola, 14 (70%, 95% CI: 46-88) achieved an objective response, and nine (45%, 95% CI: 23-68) achieved a complete response. In the diffuse large B-cell lymphoma cohort, grade 3-5 adverse events occurred in 33 (79%) of 42 patients receiving R-pina (most common were neutropenia [29%] and hyperglycemia [10%]; nine [21%] grade 5 adverse events, five of which were infection-related), and in 30 (77%) of 39 patients receiving R-pola (most common were neutropenia [23%], anemia [8%] and diarrhea [8%]; no grade 5 adverse events). In the follicular lymphoma cohort, grade 3-5 adverse events occurred in 13 (62%) of 21 patients receiving R-pina (most common were neutropenia [29%] and hyperglycemia [14%]; no grade 5 adverse events) and in ten (50%) of 20 patients receiving R-pola (most common were neutropenia [15%] and diarrhea [10%]; one grade 5 adverse event). The authors concluded that R-pina and R-pola are potential treatment options in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. Pola was selected by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response than pina, and an overall benefit-risk favoring R-pola (Morschhauser, 2019).

Population Reference No. 1 

Diffuse Large B-Cell Lymphoma -FDA Indication

For the treatment of relapsed or refractory diffuse large B cell lymphoma (DLBCL)

The GO29365 trial showed that Polivy in combination with bendamustine and rituximab improved progression-free survival and overall survival compared to bendamustine with rituximab alone.

Population Reference No. 2 

Off-label NCCN-supported uses (follicular lymphoma, mantle cell lymphoma, high-grade B-cell lymphomas, HIV-related B-cell lymphomas, and post-transplant lymphoproliferative disorder):
NCCN Guidelines v.2025 list Polivy in combination with rituximab, bendamustine with rituximab, or Polivy monotherapy as Category 2A options.

Population Reference No. 3 

Diffuse Large B-Cell Lymphoma OFF Label - NCCN Recommendation

First-line diffuse large B-cell lymphoma:
The POLARIX trial (NEJM 2022) demonstrated that Polivy in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) improved progression-free survival compared to standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.
This regimen is now recognized by NCCN v.2025 as Category 1 for first-line treatment of diffuse large B-cell lymphoma, representing a major guideline update and strengthening its clinical adoption.

Population Reference No. 4 

Folicular Lymphoma (Grade 1-2( OFF LABEL - NCCN Recommendation

Off-label NCCN-supported uses (follicular lymphoma, mantle cell lymphoma, high-grade B-cell lymphomas, HIV-related B-cell lymphomas, and post-transplant lymphoproliferative disorder):
NCCN Guidelines v.2025 list Polivy in combination with rituximab, bendamustine with rituximab, or Polivy monotherapy as Category 2A options.

Population Reference No. 5 

High-Grade B- Cell Lymphomas OFF LABEL – NCCN Recommendation

As a single agent or in combination with bendamustine and/or a rituximab product as second-line and subsequent therapy for partial response, no response, relapsed, progressive, or refractory disease after at least 2 prior therapies in non-candidates for transplant;

Population Reference No. 6 

Histologic Transformation of Nodal Marginal Zone to Diffuse Large B-Cell Lymphoma OFF LABEL – NCCN Recommendation

As a single agent or in combination with bendamustine and/or a rituximab product for individuals who have received multiple prior therapies including at least 2 lines of chemoimmunotherapy for indolent or transformed disease.

Population Reference No. 7 

Mantle Cell Lymphoma OFF LABEL – NCCN Recommendation

Mantle cell lymphoma: Polivy is not FDA-approved for mantle cell lymphoma. However, NCCN Guidelines v.2025 and NCCN Drugs & Biologics Compendia v.2025 list Polivy in combination with bendamustine and rituximab or Polivy with rituximab as a Category 2A off-label recommendation, based on limited phase II data and expert consensus (see NCCN Compendia v.2025).

Population Reference No. 8 

Post-Transplant Lymphoproliferative Disorder OFF LABEL – NCCN Recommendation

Off-label NCCN-supported uses (follicular lymphoma, mantle cell lymphoma, high-grade B-cell lymphomas, HIV-related B-cell lymphomas, and post-transplant lymphoproliferative disorder):
NCCN Guidelines v.2025 list Polivy in combination with rituximab, bendamustine with rituximab, or Polivy monotherapy as Category 2A options.

Population Reference No. 9

Bridging to CAR T-cell therapy:
NCCN v.2025 supports Polivy alone, Polivy with rituximab, or Polivy with bendamustine and rituximab as bridging regimens, especially in relapsed/refractory patients awaiting CAR T-cell infusion.

Summary Evidence

The evidence demonstrates that Polivy, whether combined with bendamustine and rituximab or with rituximab, cyclophosphamide, doxorubicin, and prednisone, provides clinically meaningful improvements in survival and health outcomes across multiple B-cell lymphoma populations. Therefore, coverage is justified under medical necessity when used according to FDA label or NCCN Compendia.

Supplemental Information

FDA initial approval: 2019 (relapsed/refractory diffuse large B-cell lymphoma).
 
FDA expanded approval: 2023 (first-line diffuse large B-cell lymphoma in combination with R-CHP).
 
Subject to compliance with Ley 79 de Puerto Rico (Pharmacy Act) and Ley 165 de Puerto Rico (Health Insurance Code).

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN) Recommendations

NCCN Guidelines v.2025 – B-Cell Lymphomas:
 
Category 1:
 
Polivy in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) for first-line treatment of diffuse large B-cell lymphoma.
 
Polivy in combination with bendamustine and rituximab for relapsed or refractory diffuse large B-cell lymphoma after two or more prior therapies.
 
 
Category 2A (Off-Label):
 
Polivy in combination with rituximab or as monotherapy for follicular lymphoma (Grade 1–2).
 
Polivy in combination with bendamustine and rituximab or Polivy with rituximab for mantle cell lymphoma (see NCCN Compendia v.2025).
 
Polivy in combination with bendamustine and rituximab for high-grade B-cell lymphomas not eligible for intensive chemotherapy.
 
Polivy in combination with rituximab or as monotherapy for HIV-related B-cell lymphomas.
 
Polivy in combination with bendamustine and rituximab or Polivy with rituximab for post-transplant lymphoproliferative disorder.
 
Polivy with or without bendamustine and rituximab as bridging therapy prior to CAR T-cell therapy.

Medicare National Coverage

No National Coverage Determination (NCD) specific to Polivy®.
 
Local Coverage Determinations (LCDs) apply for antineoplastic agents. Coverage generally follows FDA prescribing information and NCCN Compendia.

References

1. FDA Prescribing Information – Polivy (2025). U.S. Food and Drug Administration. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761121s015lbl.pdf
 
2. NCCN Guidelines v.2025 – B-Cell Lymphomas. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
  
3. NCCN Drugs & Biologics Compendium (v.2025) – Polatuzumab vedotin-piiq (Polivy). Lists mantle cell lymphoma as a Category 2A off-label recommendation. Available at: https://www.nccn.org/compendia 
 
4. CMS Medicare Coverage Database. Centers for Medicare & Medicaid Services. Available at: https://www.cms.gov/medicare-coverage-database
  
5. Sehn LH, et al. "Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma." New England Journal of Medicine, 386:351-363, 2022. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2115304 
 
6. Ley 79 – Puerto Rico Pharmacy Act. LexJuris Puerto Rico. Available at: https://www.lexjuris.com/lexlex/Leyes2019/lexl2019079.htm
 
 7. Ley 165 – Puerto Rico Health Insurance Code. Oficina de Gerencia y Presupuesto (OGP) PR. Available at: https://bvirtualogp.pr.gov/ogp/Bvirtual/LeyesOrganicas/pdf/165-2018.pdf

Codes

Applicable Modifiers

No specific modifiers apply to Polivy administration.
 
Standard chemotherapy infusion modifiers may be used when appropriate.

Policy History