Efficacy of Obinutuzumab Plus Venetoclax in Ibrutinib-Resistant MCL Observed in the Community Setting

A 73-year-old patient with relapsed/refractory (R/R) non-leukemic mantle cell lymphoma (MCL) achieved a complete response (CR) after 3 cycles of treatment with obinutuzumab (Gazyva) plus venetoclax (Venclexta) and demonstrated a lasting progression-free survival (PFS), according to a case study published in the European Journal or Haematology.¹

The patient received 6 cycles of the combination regimen, followed by obinutuzumab maintenance therapy and has remained progression-free for more than 17 months.

“To the best of our knowledge, this is the first report about obinutuzumab and venetoclax induced CR in a rituximab-intolerant patient with an ibrutinib-resistant leukemic MCL,” wrote the authors of the case study. “The combination of obinutuzumab and venetoclax might be effective for patients with and ibrutinib-resistant [R/R MCL].”

Traditional Treatment of Ibrutinib-Resistant Non-Leukemic MCL

According to the MCL international prognostic index, patients with leukemic non-nodal MCL with continued leukocytosis, have poor outcomes overall. Novel agents have been introduced into the treatment landscape in recent years to aid in the treatment of this population.

The known ORR for the third-generation humanized anti-CD20 monoclonal antibody, obinutuzumab is 27% in this patient population, according to 2013 results from the phase II GAUGUIN study. Venetoclax, a novel selective B-cell leukemia/lymphoma-2 (BCL-2) inhibitor, led to an ORR of 75% in a phase I study as monotherapy in this patient population compared with 22% ORR with temsirolimus, according to phase II data and a 28% ORR with lenalidomide, according to phase II results. Venetoclax also appears to be generally well-tolerated. Data on the combination of obinutuzumab and venetoclax remains limited in the R/R population of patients with MCL.

Outpatient Treatment of Patient With Non-Leukemic MCL

The patient presented in July 2017 with leukemic non-nodal MCL with asymptomatic leukocytosis. He had a highly elevated leukocyte count in peripheral blood and mild anemia and thrombocytopenia with a hemoglobin value of 9.4 g/dL and a platelet count of 116 000/µL. He was treated determined to have high-risk MCL and received 1 cycle of bendamustine monotherapy. Treatment was well-tolerated, and rituximab treatment was added in the second cycle of therapy, which resulted in a severe infusion reaction, cytokine release syndrome, and tumor lysis. Rituximab was stopped, and bendamustine was continued for a total of 6 cycles.

Eleven months following the primary diagnosis when the patient presented for further treatment in the hospital, progressive disease was assessed. Second-line ibrutinib was administered to the patient, but no responses occurred and the disease progressed. The patient was determined to be primary ibrutinib-resistant.

Obinutuzumab was started at 20 mg on day 1 due to a massive tumor burden and the patient’s prior history of tumor lysis syndrome. On days 2 through 4, obinutuzumab was continued at a 50 mg dose, 330 mg on day 5, and 1000 on day 6. The patient also received intravenous fluids, rasburicase, and urinary alkalization for the prevention of tumor lysis syndrome.

The laboratory analysis demonstrated a rapid decrease of leukocyte counts, and the patient developer fever of unknown origin, which was treated with antibiotics. Treatment with obinutuzumab was repeated 4 weeks later at a dose of 1000 mg once every 4 weeks. Venetoclax at a dose of 400 mg once daily was added to enhance the treatment efficacy. Venetoclax could be increased to 800 mg daily from the third cycle.

The combination of venetoclax and obinutuzumab was well tolerated. Only grade 1 leukopenia, neutropenia, anemia, and thrombocytopenia were observed. After 3 cycles of therapy, a bone marrow biopsy shows no infiltration by MCL. An abdominal ultrasound showed the patient had normal spleen size. The patient achieved a CR and continued obinutuzumab maintenance at 1000 mg every 4 weeks after 6 cycles of the combination therapy. At follow-up in July 2019, the patient had no signs of relapse.

Patients with R/R MCL are known to have a shorter PFS with ibrutinib, and the median PFS is 13.9 months. The optimal treatment approach for ibrutinib-resistant patients remains a question of debate, but venetoclax monotherapy has been shown to induce an ORR of 53%, including a CR of 18% and a partial response (PR) of 35% in patients who were pretreated with ibrutinib. For patients who are primarily resistant to the BTK inhibitor, the ORR is 38% with venetoclax.

Rationale for Obinutuzumab Plus Venetoclax in R/R MCL

Targeting BCL-2 with venetoclax may be an approach to overcoming ibrutinib resistance in patients with MCL, according to the phase I OASIS clinical trial published in Blood. The multicenter, non-randomized study evaluated the safety of obinutuzumab in combination with ibrutinib in the first part of the study, and venetoclax in combination with obinutuzumab and ibrutinib was evaluated in the second part.²

After a median follow-up of 23.5 months for part 1, 8 out of the 9 patients were still alive, and 6 had completed 2 years of treatment and were in a CR. No clinically relevant non-hematological grade 3/4 adverse events (AEs) were observed within the first 3 months of treatment, and 8 grade 3/4 hematologic AEs were reported in 4 patients, including lymphopenia and neutropenia in 4 patients each and thrombocytopenia in 1 patient.

In part 2 of the study, venetoclax was given in 3 different doses in combination with obinutuzumab and ibrutinib. Three patients received 400 mg venetoclax, 3 received 600 mg, and 6 received 800 mg. The median number of prior lines of therapy was 2 (range, 1-3), which included transplant in 8 patients.

The median follow-up was 6.5 months for living patients, and there were no clinically relevant non-hematologic grade 3/4 AEs within the first 3 months of therapy. Overall, 29 grade 3/4 hematologic AEs were observed in 7 patients, which included febrile neutropenia in 1 patient, neutropenia in 4 patients, thrombopenia in 4 patients, anemia in 2 patients, and lymphopenia in 2 patients. Five patients were in CR out of the 9 patients assessed after cycle 6.

No dose-limiting toxicities were observed in the OASIS study, and both combinations appeared well tolerated.

Based on these findings and the case study, the combination of venetoclax and obinutuzumab may be a potential treatment approach for patients with MCL who are resistant to ibrutinib. The sustained response observed in the case study remains consistent with findings of obinutuzumab plus venetoclax.¹

_References

1. _{Zhou Z, Steinhardt MJ, Düll J, et al. Obinutuzumab and venetoclax induced complete remission in a patient with ibrutinib-resistant non-nodal leukemic mantle cell lymphoma. Eur J Haematol.2020; 104: 352-355. DOI: 10.1111/ejh.13382.}
2. _{Le Gouill S, Morschhauser F, Bouabdallah K, et al. Ibrutinib plus obinutuzumab and venetoclax in relapsed/refractory mantle cells lymphoma patients, results of the OASIS phase I clinical trial. Blood. 2018; 132 (supp 1): 4158. DOI: 10.1182/blood-2018-99-11377.}