Obinutuzumab Plus DHAP Induces MRD Negativity in Transplant-Eligible Mantle Cell Lymphoma

Obinutuzumab (Gazyva) in combination with dexamethasone plus high-dose cytarabine and cisplatin (DHAP) appeared well-tolerated and generated good activity for inducing minimal residual disease (MRD) negativity in the bone marrow when used as treatment of patients with mantle cell lymphoma (MCL) who are eligible for transplant, according to findings from the phase 2 LyMa-101 study (NCT02896582).

Results also demonstrated that this regimen has potential activity as an induction chemotherapy, inducing MRD negativity in the bone marrow that could predict long-term disease control in transplant-eligible patients with treatment-naïve MCL.

“We observed superior minimal residual disease to our predefined statistical threshold, and therefore consider obinutuzumab plus DHAP to be an effective induction chemotherapy regimen,” the study authors wrote. To their knowledge, there are no published data on the use of obinutuzumab plus chemotherapy as treatment of patients with MCL, and obinutuzumab has not been investigated in combination with a high-dose cytarabine-containing regimen like DHAP.

The prospective, open-label, single-arm LyMa-101 study enrolled patients (n = 86) from 28 hospitals in France. Patients received obinutuzumab at a 1000 mg/m2 dose given intravenously (IV) on days 1, 8, and 15 at cycle 1 and day 1 at cycles 2, 3, and 4, while dexamethasone was given IV 40 mg on days 1–4, cytarabine IV at 2 g/m2 every 12 hours on day 1, and cisplatin at 100 mg/m2 by a continuous infusion over 24 hours on day 1. Instead of cisplatin, patients also could have received carboplatin or oxaliplatin as well. The regimen was administered every 21 days before transplant, followed by 3 years of obinutuzumab maintenance followed by MRD-based obinutuzumab on-demand maintenance.

The primary end point of the study was MRD negativity in the bone marrow after 4 cycles of obinutuzumab plus DHAP at the end of induction. If the MRD negativity was 70% or more by intention to treat, the regimen was considered effective.

Overall, 81 patients (95%) completed the induction therapy, 73 (86%) underwent an autologous stem cell transplantation (SCT), and 69 (81%) had started maintenance therapy on the study. The median time from diagnosis to the start of induction was 1.1 months (interquartile range, 0.7-1.7). Eight patients (9%) received cisplatin, including 3 who changed over to carboplatin and 2 to oxaliplatin during induction, 35 (41%) received carboplatin, and 42 (49%) received oxaliplatin. Two patients (2%) had progressed during induction therapy.

Thirteen patients (15%) were not evaluable for MRD as they had purely nodal disease with no detectable MCL clone in either the peripheral blood or bone marrow. The mean infiltration was 24% (range, 0.06-100.0) in bone marrow and 20% (range, 0.4-93.0) in the peripheral blood. Three patients (4%) had stopped treatment before received 4 cycles due to adverse events (AEs), which included peritonitis, infusion-related syndrome, and febrile neutropenia, and an unsuccessful bone marrow evaluation in 1 patient. Additionally, 2 patients (3%) progressed before the end of induction therapy. A bone marrow assessment was conducted on the remaining 67 patients (92%) at the end of induction.

Among these 67 patients, 12 (18%) had MRD positivity in their bone marrow, which included 3 (4%) with quantifiable positive above 0.0001% –0.01%. The MCL International Prognostic Index score was low in 7 (58%) of the 12 patients, intermediate in 3 (25%), and high in 2 (17%). Two of these patients showed a below quantitative range clone in the peripheral blood.

Fourteen patients (19%) of the 73 patients did not achieve clinical or molecular complete response (CR) at the end of induction, and 55 (75%) reached MRD negativity in the bone marrow at the end of induction. One bone marrow-negative patients was peripheral blood-positive below the quantitative range with confirmation of positivity in the peripheral blood (1x10-5), and this patient did not demonstrate any clinical or histological high-risk features.

Eighteen patients (25%) were MRD-positive according to the protocol definition, and among patients with MRD quantification in bone marrow at the end of induction, 55 (82%) reached MRD negativity in the bone marrow. Overall, 63 patients (96%) reached MRD negativity in the peripheral blood.

Overall responses were observed in 78 patients (92%), including 52 (61%) who had a CR, and according to Lugano criteria, 67 (79%) had achieved a CR.

Eighty (94%) remained progression-free at 12 months (95% CI, 84.7-97.2), and 82 (96%) survived at 12 months (95% CI, 88.1-98.7). At 12 months, none of the 12 patients who had MRD positivity had relapsed, and the only patient to progress was MRD0negative in the bone marrow and peripheral blood at the end of induction therapy.

Investigators noted that the TP53 mutational status, an exploratory end point of the study, was abnormal per next-generation sequencing (NGS) or immunohistochemistry (IHC) in 2 (15%) of the 13 patients who were MRD-positive, which included the single peripheral blood-positive/bone marrow-negative patient. Resistance or early progression was observed in 3 patients, 1 (33%) with a TP53 mutation on NGS, 1 patient with a TP53mutation by IHC, and 1 was Ki67-positive by IHC, so all 3 patients had high-risk diagnostic features.

The main reason for stopping treatment on the study before autologous SCT was AEs. The most common grade 3 and grade 4, respectively, treatment-emergent AEs included anemia in 31% and 4% of patients, neutropenia in 15% and 38%.

A total of 58 serious AEs (SAEs) occurred in the induction phase, and 2 patients had renal failure, both of whom had received cisplatin. The most common SAEs included infection (9%), gastrointestinal disorders (6%), and general disorders with fever (6%).

Obinutuzumab was discontinued in 28 patients who had presented with 74 AEs, of which 43 were related to obinutuzumab in 21 patients. All AEs that led to discontinuation occurred during cycle 1; the main reason was grade 3/4 thrombocytopenia (26%).

Treatment discontinuation occurred due to 25 AEs, 13 of which occurred during induction, 5 during autologous SCT, and 7 during maintenance, in 14 patients (16%). Nine patients (11%) stopped maintenance due to medical decision, death, myelodysplasia, myeloproliferative neoplasm, and progression, and 4 AEs in 4 patients (Hemophilus influenzae, pneumonia, hepatic cytolysis, and diarrhea).

On this study, 3 patients (4%) died, due to MCL, myocardial infarction, and intracerebral hemorrhage, but these deaths were not deemed related to obinutuzumab.

Overall, the combination of obinutuzumab with DHAP appeared to provide a high level of MRD negativity in bone marrow as induction in transplant-eligible patients with MCL. The LyMa-101 study achieved its primary end point, demonstrating the potential activity of this regimen, as well as the potential predictive value of bone marrow MRD negativity on long-term disease control.

_Reference

_{Le Gouill S, Beldi-Ferchiou A, Alcantara M, et al. Molecular response after obinutuzumab plus high-dose cytarabine induction for transplant-eligible patients with untreated mantle cell lymphoma (LyMa-101): a phase 2 trial of the LYSA group [Published Online: September 21, 2020]. Lancet Hematol. doi: 10.1016/S2352-3026(10)30291-x}