Maintenance Rituximab/Bortezomib Demonstrates 90.2% DFS at 2 Years in MCL

Robert W. Chen, MD

Robert W. Chen, MD

The addition of bortezomib (Velcade) to rituximab (Rituxan) as a maintenance therapy following consolidative autologous hematopoietic stem cell transplantation (auto-HCT) may improve disease-free survival (DFS) and overall survival (OS) in patients with mantle cell lymphoma (MCL), results of a small phase II study suggest.

After a median follow-up of 35.9 months, the 2-year DFS rate with the combination was 90.2% (95% CI, 66%-97%) and the 2-year OS rate was 94.7% (95% CI, 68%-99%). In patients who received induction therapy followed by auto-HCT and rituximab/bortezomib maintenance in first complete response (CR), the 2-year DFS rate was 93.8% (95% CI, 63%—99%) and the 2-year OS rate was 92.3% (95% CI, 57%-99%).

“In this multicenter phase II prospective trial, we showed that the combination of rituximab and bortezomib as maintenance therapy post-consolidative auto-HCT is feasible, well tolerated, and yielded a 2-year DFS of 90.2%,” lead investigator Robert W. Chen, MD, associate director, Toni Stephenson Lymphoma Center, City of Hope, and colleagues wrote in the results published in theJournal of Hematology & Oncology.

Between September 2011 and October 2016, the open-label, multi-center, single-arm, phase II trial enrolled 23 patients with MCL who had undergone consolidative auto-HCT. Patients received subcutaneous bortezomib at a weekly dose of 1.3 mg/m²for 4 weeks every 3 months, and weekly intravenous rituximab at a dose of 375 mg/m²for 4 weeks every 6 months, both up to 24 months.

To be eligible for enrollment on the study, patients had to be ≥18 years old with a Karnofsky performance score of ≥60%, and have histologically documented or cytologically confirmed MCL. Patients were also required to have presence of cyclin D1 (CCND1) confirmed by either fluorescence in situ hybridization (FISH) or immunohistochemical staining. Additionally, patients had to have undergone auto-HCT with documented CR between 60 and 180 days following auto-HCT by either CT or CT/PET, and to have started treatment between 60 and 180 days after auto-HCT.

Patients were excluded from the study if they had ≥grade 2 neuropathy prior to receiving bortezomib, prior hypersensitivity reaction to bortezomib, positive serology for HIV or active hepatitis B or C, active cardiac disease, abnormal liver or renal function, or concurrent or previous diagnosis of cancer.

The majority of the patients were male (96%) with a considerably young median age of 59 years (range, 45—66). Most of the patients received auto-HCT in CR1 (83%) and had advanced-stage MCL at diagnosis (70% stage IV). Of the 23 patients, 10 had low-risk disease and 12 had intermediate-risk disease by the mantle cell international prognostic index (MIPI).

Investigators performed CT imaging and/or FDG-PET and bone marrow biopsy every 6 months for the first 2 years patients were treated, then yearly thereafter. The trial was closed prematurely due to slow accrual, with a total of 23 out of a planned 34 patients. All 23 patients were evaluable for response.

Patients received a median of 8 cycles of the combination, with each cycle lasting 3 months. The median time patients stayed on therapy was 19.9 months.

The primary endpoint of the trial was DFS and secondary endpoints included toxicity, relapse rate, OS, and expression of CCND1 mRNA in minimal residual disease monitoring. The historical 2-year DFS probability in MCL patients treated with rituximab alone was approximately 60%, according to data from City of Hope prior to 2010 that was unpublished at the time of the study design. This trial aimed to detect a 20% improvement in DFS at 2 years.

As the trial did not reach full accrual of 34 patients, it was ultimately underpowered per the trial design. However, the estimated 2-year DFS of 90.2% exceeded the desired result of 80% DFS, the investigators concluded.

Investigators reported the most common grade 3 or 4 toxicities were neutropenia (74%), lymphopenia (35%), pneumonia (9%), anemia (9%), skin infections (4%), hypertension (4%), and thrombocytopenia (4%). Grade 1 peripheral neuropathy occurred in 11 patients (48%) and grade 2 events occurred in 2 patients (9%). No grade 3 or 4 peripheral neuropathies were reported. One patient developed myelodysplastic syndrome (MDS). There were 3 deaths—2 from relapsed MCL and 1 from allogeneic HCT for MDS.

“As our trial was the first to study the combination regimen of rituximab and bortezomib in a post-auto-HCT population, there was a concern of tolerability. However, we found that the combination was well tolerated; no patients withdrew from the study due to adverse events. And, with the exception of hematological toxicities, there were few grade 3 or 4 events,” Chen et al wrote.

Investigators assessed CCND1 mRNA in samples of peripheral blood collected at baseline and on day 1 of each cycle.

Disease monitoring was performed on 18 patients at baseline and 12 later time points ranging from 1 to 60 months. High CCND1 mRNA (15600%) was detected in an untreated patient with MCL and low CCND1 mRNA (10%) was detected in a normal healthy control.

Of the 151 samples, with 1 to 13 samples per patient, 2 samples were >10% (2/151; 1.3%) and 9 samples were >5% (9/151; 6.0%) (range, 0%-11.6%). At baseline, CCND1 mRNA had a mean of 2.7% (range, 0.8%—6.1%). The average CCND1 mRNA within a patient had a mean of 2.3% (range, 0.9–4.7%).

“As this trial started with patients in remission, and there were relatively few relapses, we were not able to correlate progression with rising CCND1 mRNA levels,” the investigators commented. “Therefore, we could not comment on the sensitivity of this method.”

One patient developed progressive disease due to withdrawal of consent prior to relapse and the other developed progressive disease due to urgent start of treatment. No samples were obtained from these patients. CCND1 mRNA remained low for all patients in remission.

Reference:

Chen RW, Palmer AM, Tomassetti S, et al. Multi-center phase II trial of bortezomib and rituximab maintenance combination therapy in patients with mantle cell lymphoma after consolidative autologous stem cell transplantation.J Hematol Oncol. 2018;11:87. doi: 10.1186/s13045-018-0631-3.