Bortezomib Maintenance Fails to Improve Transplant Outcomes in Newly Diagnosed Mantle Cell Lymphoma

Apr 14, 2020

Bortezomib as maintenance therapy following autologous stem cell transplant did not demonstrate a positive effect as treatment of young newly diagnosed patients with mantle cell lymphoma, according to the results of the phase II HOVON trial.

Bortezomib (Velcade) as maintenance therapy following autologous stem cell transplant (ASCT) did not demonstrate a positive effect as treatment of young newly diagnosed patients with mantle cell lymphoma (MCL), according to the results of the phase II HOVON trial.

Five-year event-free survival (EFS) was similar between the 2 arms at 63% in the bortezomib arm (95% CI, 44-78;P=.73) versus 60% in the control arm (95% CI, 40-75). Five-year overall survival (OS) was identical with 90% in both arms (95% CI, 72-97).

“In conclusion, although the outcome of young patients with MCL is still improving, the absence of a plateau in the EFS after induction therapy, including ASCT, demands both improvements in the induction therapy and interventions thereafter,” Jeanette K. Doorduijn, MD, PhD, Haematology, Erasmus MC Cancer Centre, Rotterdam, Netherlands, et al wrote.

With a median follow-up of 77.5 months among all patients alive, the 5-year EFS was 51%, and the 5-year OS was 73%. The 2-year EFS was 83% in the bortezomib arm (95% CI, 65-93) compared with 80% in the arm without maintenance (95% CI, 61-90).

Overall, 50 patients died (37%), and the causes of death were MCL in 26 patients (52%), secondary malignancy in 4 patients (8%), treatment-related in 1 patient (2%), unknown in 4 patients (8%), and other in 10 patients (20%). Seven of the 10 patients in the ladder category died due to complications from allogeneic stem cell transplant.

No unexpected toxicities were observed, according to data from an interim analysis performed in October 2011. This analysis was based on data from 30 randomized patients with at least 3 months of follow-up after randomization.

The median duration of bortezomib maintenance was 21 months. Fifteen of 30 patients randomized to bortezomib maintenance continued therapy as planned for 24 months, while 15 patients received bortezomib for a median of 14 months (range, 0-23). Reasons for discontinuation were progressive disease in 4 patients, excessive toxicity in 6 patients, refusal to start in 2 patients, refusal to continue after the first dose in 1 patient, secondary malignancy in 1 patient, and unknown in 1 patient.

Grade 2 neurological adverse events (AEs) occurred in 4 patients, and grade 3 was observed in 1 patient. Grade 4 neurological AEs were not observed.

Overall, 15 patients (11%) developed a second malignancy, of which 6 had received bortezomib maintenance. These secondary malignancies included non-melanoma skin cancer in 2 patients and melanoma, prostate cancer, oropharynx carcinoma, and neuroendocrine carcinoma in 1 patient each. Among the 9 patients in the observation arm who developed a secondary malignancy, these included non-melanoma skin cancer in 4 patients, adenocarcinoma in 3 patients, and lung cancer in 2 patients.

HOVON was an investigator-initiated, multicenter study that was conducted at 15 centers in the Netherlands. Stratification factors according to baseline characteristics were not defined.

To be included in the study, patients had to have newly diagnosed MCL, Ann Arbor stage II to IV, a WHO performance status of 0 to 2, and measurable disease. Some exclusion criteria for this study included creatinine clearance <50 ml/min, CNS involvement, HIV or hepatitis B or C positivity, and peripheral neuropathy > grade 2. Patients also could not have an active malignancy or other serious medical condition that may interfere with study treatment.

Treatment included 3 cycles of rituximab (Rituxan), cyclophosphamide doxorubicin, vincristine, and prednisone (R-CHOP21), followed by 2 cycles of high dose cytarabine (ARA-C) and rituximab on day 11. One cytarabine cycle was used for stem cell mobilization with G-CSF, which was planned to start on day 8. Investigators noted at least 3 × 106 CD34 + cells/kg were considered sufficient for ASCT.

Patients who achieved a partial response or complete response after the second cycle of cytarabine continued to ASCT after BEAM conditioning, and all other patients went off protocol.

Patients were then randomized 1:1 to receive bortezomib maintenance or no further treatment. Bortezomib was administered at 1.3 mg/m2intravenous doses once every 2 weeks for 2 years, beginning between 6 and 12 weeks after ASCT. Treatment was stopped if the disease progressed or patient relapsed, as well as if maintenance was interrupted for more than 6 weeks.

“Our study confirmed the important role of ARA‐C in the induction of young MCL patients. There was no indication that bortezomib maintenance after ASCT may improve the outcome of MCL patients after ASCT,” study authors concluded. “Other options, especially BTK inhibitors such as ibrutinib [Imbruvica], may be explored to reduce relapse after ASCT.”

A number of BTK inhibitors, such as ibrutinib, have been approved by the FDA for the treatment of patients with MCL. These agents have demonstrated durable responses in this patient population. Most recently,zanubrutinib (Brukinsa) received its approval from the FDAfor the treatment of patients with MCL who have received at least 1 prior line of therapy.

Reference:

Doorduijn JK, Zijlstra JM, Lugtenburg PJ, et al. Bortezomib maintenance after R‐CHOP, cytarabine and autologous stem cell transplantation in newly diagnosed patients with mantle cell lymphoma, results of a randomised phase II HOVON trial [Published Online March 9, 2020].Wiley. DOI:10.1111/bjh.16567.

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