Polatuzumab Vedotin-Piiq for Previously Untreated Diffuse Large B-Cell Lymphoma Not Otherwise Specified & High-Grade B-Cell Lymphoma
The FDA approved polatuzumab vedotin-piiq with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for 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 (IPI) score of 2 or greater.
Approval was based on POLARIX (NCT03274492), a randomized, double-blind, placebo-controlled trial in 879 patients with previously untreated large B-cell lymphoma and an IPI score of 2-5. The trial evaluated the superiority of substituting polatuzumab vedotin for vincristine in the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen. Patients were randomized (1:1) to receive either polatuzumab vedotin plus R-CHP (pola + R-CHP) or R-CHOP for six 21-day cycles, followed by two additional cycles of rituximab alone in both arms. The main diagnoses were de novo DLBCL, NOS (84%), and HGBL (11%).
Efficacy was based on investigator-assessed progression-free survival (PFS). PFS was statistically significantly longer in the pola + R-CHP arm, with a hazard ratio (HR) of 0.73 (95% CI: 0.57, 0.95; p=0.0177). This arm also had a statistically significant improvement in modified event-free survival (HR: 0.75; 95% CI: 0.58, 0.96; p=0.0244). No significant difference in complete response rate or overall survival (HR: 0.94; 95% CI: 0.67, 1.33 on final analysis) was observed.
The most common adverse reactions with pola + R-CHP (>=20%), excluding laboratory abnormalities, were peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis. Grade 3-4 laboratory abnormalities (>=10%) were lymphopenia, neutropenia, hyperuricemia, and anemia. Peripheral neuropathy developed or worsened in 53 percent of patients with resolution in 58 percent after a median of 4 months. Serious adverse reactions occurred in 34 percent of patients, including febrile neutropenia and pneumonia.
The recommended dose of polatuzumab vedotin is 1.8 mg/kg as an intravenous infusion every 21 days for 6 cycles in combination with R-CHP. Patients should be premedicated with an antihistamine and antipyretic and receive prophylactic granulocyte colony-stimulating factor.
Neutrophil Recovery & Infection In Hematologic Malignancies
Omidubicel-onlv has been approved for use in adult and pediatric patients (12 years and older) with hematologic malignancies who are planned for umbilical cord blood transplantation following myeloablative conditioning to reduce the time to neutrophil recovery and the incidence of infection.
Safety and efficacy were evaluated in Study P0501 (NCT02730299), an open-label, multicenter, randomized trial of omidubicel-onlv transplantation or unmanipulated cord blood (UCB) unit transplantation following myeloablative conditioning in patients with hematologic malignancies. In total, 125 patients were randomized-62 patients to receive omidubicel-onlv and 63 to the UCB group. Fifty-two patients were transplanted with omidubicel-onlv receiving a median CD34+ cell dose of 9.0 x 106 cells/kg (Range: 2.1-47.6 x 106 cells/kg). Fifty-six patients were transplanted in the UCB arm with one or two cord units (66% received two cord units). In the 42 patients with reported post-thaw cell dose, the median CD34+ cell dose was 0.2 x 106 cells/Kg (Range: 0.0-0.8 x 106 cells/kg). Multiple conditioning regimens were used, including total body irradiation-based or chemotherapy-based options.
The main efficacy outcome measures were time to neutrophil recovery following transplantation and the incidence of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Grade 2/3 bacterial or Grade 3 fungal infections through Day 100 post-transplantation. The median time to neutrophil recovery was 12 days for those receiving omidubicel-onlv (95% CI: 10-15 days) and 22 days in the UCB arm (95% CI: 19-25 Days). Eighty-seven percent in the omidubicel-onlv arm and 83 percent in the UCB arm achieved neutrophil recovery. The incidence of BMT CTN Grade 2/3 bacterial or Grade 3 fungal infections through Day 100 post-transplantation was 39 percent and 60 percent, respectively, in the two groups.
Similar to approved UCB products, the prescribing information contains a boxed warning for fatal or life-threatening infusion reactions, graft-versus-host disease (GVHD), engraftment syndrome, and graft failure. Among 117 patients who received omidubicel-onlv for any disease, infusion reactions occurred in 47 percent of patients, acute GVHD in 58 percent, chronic GVHD in 35 percent, and graft failure in 3 percent. In patients with hematologic malignancies in study P0501, the most common Grade 3-5 adverse reactions were pain (33%), mucosal inflammation (31%), hypertension (25%), and gastrointestinal toxicity (19%).
The recommended omidubicel-onlv dose is two sequential infusions consisting of the following:
* Cultured fraction: A minimum of 8.0 x 108 total viable cells with a minimum of 8.7 percent CD34+ cells and a minimum of 9.2 x 107 total CD34+ cells, followed by
* Non-cultured fraction: A minimum of 4.0 x 108 total viable cells with a minimum of 2.4 x 107 CD3+ cells.