No Clinical Benefit Added Using Auto-HCT/Rituximab in MCL Cohort

"In this initial analysis, in the era of highly effective induction and maintenance regimens, [patients with] mantle cell lymphoma in first complete response with undetectable MRD did not benefit from consolidative autologous transplant. Longer follow-up will be important to confirm these findings," according to study author Timothy Fenske, MD, MS.

No additional efficacy was noted among patients with mantle cell lymphoma (MCL) in first complete remission (CR) with undetectable minimal residual disease (uMRD) when combining rituximab (Rituxan) with consolidative autologous hematopoietic cell transplant (auto-HCT), according to data from the phase 3 ECOG-ACRIN EA4151/BMT-CTN 1601 trial (NCT03267433) presented at the 2024 American Society of Hematology Annual Meeting & Exposition (ASH).1

Data showed that, at a median follow-up of 2.7 years, the estimated hazard ratio for overall survival (OS) for auto-HCT plus rituximab and rituximab alone in all randomized patients (n = 516) and those who were treated as assigned (n = 375) were 1.11 (95% CI, 0.71-1.74; P = .66) and 1.00 (95% CI, 0.58-1.74; P = .99), respectively, crossing the futility boundary for OS.

In all randomized patients, the 3-year OS rate was 82.1% for auto-HCT plus rituximab compared with 82.7% in the rituximab-alone arm; these rates were 86.2% vs 84.8% in the treated-as-assigned group.

“This means that the probability of detecting significant difference, even when the study is more fully read out, is highly improbable,” lead study author Timothy Fenske, MD, MS, a medical oncologist at Medical College of Wisconsin, said in an oral presentation during the meeting. “In this initial analysis, in the era of highly effective induction and maintenance regimens, [patients with] mantle cell lymphoma in first complete response with undetectable MRD did not benefit from consolidative autologous transplant. Longer follow-up will be important to confirm these findings.”

AutoHCT is often given for patients with MCL who are in their first CR, based on prior data.2-5 However, retrospective and real-world studies have explored whether there is a benefit to auto-HCT in this patient population.6 For example, in the TRIANGLE trial (NCT02858258), results showed that auto-HCT did not show a benefit when added to induction and maintenance therapy regimens containing high-dose cytarabine, rituximab, and ibrutinib (Imbruvica).7

In the 4-arm, EA4151/BMT-CTN 1601 trial, investigators evaluated whether auto-HCT has a benefit in patients achieving deep first remission, which is measured by the immunoglobulin high throughput sequencing MRD assay clonoSEQ with sensitivity to 1 x 10-6.

To be eligible for enrollment, patients with MCL must have been between the ages of 18 and 70 years and in first remission. Rituximab-containing induction regimens were permitted and included those with BTK inhibitors.

Patients could be enrolled on study before, during, or after induction therapies. If clonal markers were present in molecular testing, patients went to post-induction restaging and submission of blood for MRD assessment; if no markers were found, they were identified as MRD indeterminate.

Patients who had an MRD-negative CR underwent randomization to auto-HCT plus rituximab for 3 years (arm A; n = 257), or rituximab alone for 3 years (arm B; n = 259). Those who had a partial response (MRD-positive or -negative) or an MRD-positive CR went onto the registration cohort and received autoHCT plus rituximab for 3 years (arm C; n = 49); those who had been deemed MRD indeterminate also had autoHCT plus rituximab for 3 years (arm D; n = 85).

Stratification factors in the randomization cohort included Mantle Cell Lymphoma International Prognostic Index (MIPI)-c and intensive vs non-intensive induction therapy.

The primary end point was OS between the auto-HCT plus maintenance rituximab vs maintenance rituximab alone; secondary measures included progression-free survival (PFS) in arm A vs arm B, as well as PFS in arms C and D and conversion rate of MRD-positive patients in arm C to uMRD following auto-HCT.

Investigators assumed a 6-year OS rate of 76% in the standard rituximab maintenance arm and targeted to detect a 10% improvement to 86% at 6 years when auto-HCT was added. The futility boundary was an OS hazard ratio of 0.984 for arm A vs B.

The third preplanned interim analysis had a data cutoff date of July 15, 2024, and included a median follow-up of 2.7 years. Fenske noted that, in September 2024, the Data Safety Monitoring Committee recommended termination of study accrual and release of findings based on the analysis.

Between August 2017 and July 15, 2024, 650 patients were enrolled. The median age was 60 years (range, 27-71), 79% of patients were male, most were White (92%), and 35% had elevated lactate dehydrogenase. Thirty-seven percent of patients had a MIPI-c score labeled as high/high-intermediate and 73% had intensive induction therapy. A total 7.2% of patients received a BTK inhibitor as induction treatment vs 0.3% who received one as maintenance therapy.

The primary analysis population included all randomized patients, but a treated-as-assigned analysis was also conducted as 25.3% of patients in arm A and 0.8% in arm B refused their assigned treatment.

Additional findings showed that there was also no significant difference observed in PFS outcomes between arms A and B. In the all-randomized cohort, the hazard ratio for PFS was 1.05 (95% CI, 0.71-1.56; P = .79); in the treated-as-assigned group, the hazard ratio was 0.95 (95% CI, 0.59-1.54; P = .84). Three-year PFS rates in the all-randomized group were 76.6% and 77.4% for arms A and B, respectively; these rates were 81.5% and 80.4%, respectively, in the treated-as-assigned group.

OS was also analyzed between arms A and B by MIPI-c score. For those with a MIPI-c low/LI group, the 3-year OS rate was 84.6% for arm A compared with 85.7% for arm B (P = .96). In patients who had a MIPI-c high/HI group, the rates were 77.4% and 77.6% (P = .71).

When OS was measured between arms A and B comparing induction therapy intensity, it was found that the 3-year OS rates were 83.0% for arm A vs 86.2% for arm B (P = .30). In the non-intensive induction group, the 3-year OS rates were 79.5% vs 72.8%, respectively (P = .48).

“As we might expect, the survival appears somewhat superior in patients receiving intensive induction; however, receipt of autologous transplant was not associated with a significant improvement in overall survival regardless of induction intensity.”

OS was also evaluated in patients who were enrolled in arms C and D. Here, the 3-year OS rates were 81.9% (95% CI, 69.6%-96.4%) and 85.1% (95% CI, 76.0%-95.4%), respectively. Three-year PFS rates were 76.9% (95% CI, 64.4%-91.7%) and 73.4% (95% CI, 62.7%-85.9%), respectively.

Investigators conducted an exploratory analysis of the MRD-positive patients that comprised arm C of posttransplant MRD status. Data showed that the 3-year OS rate in patients who converted to uMRD6 posttransplant (n = 17) was 100% compared with 63.6% in those who stayed MRD positive. The 3-year PFS rates were similar at 100% vs 48.8%, respectively, “suggesting that MRD-positive patients may still benefit from autologous transplant,” Fenske said, noting the small subgroup size.

Thirty-four deaths were reported on study, occurring from lymphoma (arm A, 4.7%; arm B, 3.5%; arm C, 2.0%; arm D, 2.4%), COVID-19 (5.1%; 6.6%; 2.0%; 3.5%), other (3.5%; 3.1%; 6.1%; 5.8%), and unknown causes (1.6%; 1.5%; 2.0%; N/A).

Disclosures: Fenske cited honoraria from AbbVie, Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, Beigene, Janssen, Kite, Lilly, Ono Pharmaceuticals, AstraZeneca, SeaGen, and Bayer; speakers bureau roles from AstraZeneca, Beigene, Kite, and Seagen; and consulting roles with AbbVie, Adapative Biotechnolgoies, ADC Therapeutics, AstraZeneca, Beigene, Janssen, Kite, Ono Pharmaceuticals, SeaGen, and Bayer.

References

1. Fenske T, Wang XV, Till BG, et al. Lack of benefit of autologous hematopoietic cell transplantation (auto-HCT) in mantle cell lymphoma (MCL) patients (pts) in first complete remission (CR) with undetectable minimal residual disease (uMRD): initial report from the ECOG-ACRIN EA4151 phase 3 randomized trial. Blood. 2024;144(supplement 2):LBA-6. doi:10.1182/blood-2024-212973
2. Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005105(7):2677-2684. doi: 10.1182/blood-2004-10-3883
3. Eskelund CW, Kolstad A, Jerkeman M, et al. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau.Br J Haem. 2016;175(3):410-418. doi: 10.1111/bjh.14241
4. Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network.Lancet. 2016. 388(10044):565-575. doi:10.1016/S0140-6736(16)00739-X
5. Damon LE, Johnson JL, Niedzwiecki D, et al. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909.J Clin Oncol. 2009;27(36):6101-6108. doi:10.1200/JCO.2009.22.2554
6. Martin P, Cohen JB, Wang M, et al. Treatment outcomes and roles of transplantation and maintenance rituximab in patients with previously untreated mantle cell lymphoma: results from large real-world cohorts.J Clin Oncol. 2023;41(3):41(3):541-554. doi:10.1200/JCO.21.02698
7. Dreyling M, Doorduijn J, Giné E, et al. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024;403(10441):2293-2306. doi:10.1016/S0140-6736(24)00184-3