Tolerability of 2-Weekly CHOP+Rituximab Followed by Yttrium-90 Ibritumomab Tiuxetan (Zevalin) In Patients with Previously Untreated Diffuse Large B Cell Lymphoma (DLBCL): Final Analysis

Improved outcomes have been demonstrated in DLBCL with dose dense CHOP (CHOP-14), the addition of immunotherapy to CHOP, and radioimmunotherapy consolidation following CHOP chemotherapy. A prospective, single-arm, open-label, nonrandomized phase II trial was conducted using a combination of the above with dose dense CHOP+R, every 2 weeks, followed by radioimmunotherapy consolidation to evaluate its efficacy and safety in untreated DLBCL patients.

20 eligible patients (measurable disease, age >18 years, performance status 0–2, adequate marrow, liver and kidney function) with previously untreated DLBCL were enrolled. Patients with transformed lymphoma were excluded. Patients received standard CHOP along with rituximab 375mg/m2 IV on day 1, every two weeks for 6 cycles, followed by Zevalin 6–8 weeks later.

In 20 treated patients, ORR was 100% with 90% CR and 10% PR. 16 patients received the entire treatment regimen as intended. 3 patients (15%) relapsed. All relapses were retreated with one patient now in CR and 2 deceased. One other patient, who did not receive Zevalin, is also deceased from organizing pneumonia 2 years after last chemotherapy.

The most common adverse effects of this regimen were hematological. All patients (n=20) had anemia during CHOP+R pre-Zevalin, 15 (75%) patients with grade 1/2 and 5 (25%) with grade 3 anemia. 11 patients had thrombocytopenia, 4 with grade 3/4 toxicity. Neutropenia was present during CHOP+R therapy in 14 patients (70%), 2 cases of grade 2 and 12 cases of grade 4 toxicity. However, neutropenic fever only occurred in 4 patients, all with grade 1/2 neutropenia. Neuropathy was also a common toxicity (15 patients), with grade 3 toxicity occurring in 4 patients. Less common adverse effects, all ≤ grade 2, included anorexia, constipation, nephrolithiasis, diarrhea, urinary frequency, dysgeusia and rhinitis. With completion of dose dense chemotherapy, one patient had organizing pneumonia, one had grade 2 pneumonitis, and one had bronchiectasis, all precluding the use of Zevalin. Pre and post chemotherapy MUGA scans demonstrated stable left ventricular ejection fractions in all but one patient, who remains in CR. Zevalin was completed by 16 patients (80%). Zevalin induced grade 3/4 cytopenias occurred in 8 patients (50%), the most common being neutropenia (all 8 patients) with no cases of neutropenic fever. 12 (75%) patients experienced thrombocytopenia, though only 2 had grade 3/4 effects. Grade 3 syncope occurred in one patient. All other non-hematologic effects were ≤ grade 2 and included neuropathy, sinus and yeast infections, folliculitis, rash, diarrhea, nausea, and urinary incontinence.

Consolidation with Zevalin radioimmunotherapy following dose dense CHOP+R therapy is well tolerated, safe and non-life threatening among our sample population of untreated DLBCL.

Off Label Use: Chemotherapy with R-CHOP every 21 days is the standard of care for DLBCL in the front-line setting. We are administering R-CHOP every 14 days for dose intensification followed by zevalin (radioimmunotherapy) consolidation for untreated DLBCL. This regimen is off-label. Gregory: Amgen: Consultancy; Astellas: Research Funding; Celgene: Research Funding; Cephalon: Research Funding, Speakers Bureau; Genentech (Roche): Consultancy, Research Funding, Speakers Bureau; Glaxo-Smith-Kline: Research Funding; Immunomedics: Research Funding; NCIC CTG: Research Funding; Novartis: Consultancy, Research Funding; Onyx (Proteolix): Research Funding; Spectrum Pharmaceuticals: Consultancy.