Autologous HCT Shows No Benefit for Patients With MCL in First Complete Remission

Timothy S. Fenske, MD, MS

(Credit: Medical College of Wisconsin)

Data from an interim analysis of the phase 3 ECOG-ACRIN EA4151 clinical trial (NCT03267433) suggest that patients with mantle cell lymphoma (MCL) who are in first complete remission (CR) did not benefit from consolidative autologous hematopoietic cell transplantation (auto-HCT).¹ The data were presented by Timothy S. Fenske, MD, MS, at the 66th American Society of Hematology (ASH) Annual Meeting, held December 7-10, 2024, in San Diego, California.

The study aimed to explore whether auto-HCT benefits patients achieving deep first remission, as measured by a highly sensitive immunoglobulin high throughput sequencing minimal residual disease (MRD) assay. The trial organized the included patients into 4 cohorts: Cohorts A (n = 257) and B (n = 259), which consisted of patients in CR with undetectable MRD at 1 in 10^-6 sensitivity (uMRD6) randomly assigned 1:1 to receive auto-HCT plus maintenance rituximab (cohort A) or maintenance rituximab alone (cohort B), with individuals stratified by MIPI-c score and intensive vs non-intensive induction; Cohort C (n = 49) included patients who were in CR with MRD-positive, while those who were in CR with MRD-indeterminate were placed in Cohort D (n = 85), both of which received auto-HCT plus maintenance rituximab.

The overall survival (OS) and progression-free survival (PFS) rates for the A and B groups were 82.1% and 82.7%, respectively, for all randomized patients, rising slightly to 86.2% and 84.8% for the treated-as-assigned analysis (65 patients [25.3%] in Cohort A and 2 patients [0.8%] in Cohort B refused their assigned treatment). The 3-year PFS for the A and B groups were 76.6% and 77.4% in all randomized patients, and 81.5% and 80.4% in the treated-as-assigned patients, respectively.

At a median follow-up of 2.7 years, the OS hazard ratio for Cohort A vs Cohort B crossed the futility boundary (HR, 1.11; 95% CI, 0.71–1.74; P = .66). The estimated PFS hazard ratio between the Cohorts A and B was 1.05 (95% CI, 0.71-1.56; P = .79) in all randomized patients and 0.95 (95% CI, 0.59-1.54; P = .84) in the treated-as-assigned analysis.

“In the era of highly effective induction and maintenance regimens, MCL patients in first CR with undetectable MRD did not benefit,” Fenske, a professor of hematology and medical oncology at the Medical College of Wisconsin, said in his presentation, emphasizing that longer follow-up would be needed to confirm the data. “Patients who remain MRD positive after induction may benefit from auto-transplant, particularly the patients who converted to undetectable MRD post-transplant, who appeared to have improved survival and progression-free survival.”

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The exploratory analysis of Cohorts C and D suggested that among those in Cohort C, conversion to uMRD6 after auto-HCT (n = 17) correlated with superior outcomes, with 3-year OS and PFS of 100% for those individuals. Comparatively, those who remained MRD-positive post-transplant (n = 13) had 3-year OS and PFS rates of just 63.6% and 48.8%, respectively.

“The numbers here are relatively small, so I would consider this an exploratory analysis, but it does suggest perhaps that patients who remain MRD positive following induction may still benefit from autologous transplant,” Fenske said. Overall, for Cohort C, the 3-year OS and PFS rates were 81.9% (95% CI, 69.6-96.4) and 76.9% (95% CI, 64.4-91.7), respectively; for Arm D, they were 85.1% (95% CI, 76.0-95.4) and 73.4% (95% CI, 62.7-85.9), respectively.

For those who were stratified to the combined MCL International Prognostic Index (MIPI-c) low or low-intermediate subgroups, the OS rate at 3 years was 84.6% vs 85.7% for Cohort A vs B (P = .96), respectively, while in the MIPI-c high/high-intermediate groups, the 3-year OS was 77.4% vs 77.6% for Cohort A vs B (P = .71), respectively. Among those in the intensive induction group, the respective OS rates were 83.0% vs 86.2% for Cohort A vs B (P = .30), while in the nonintensive induction group, the respective OS rates were 79.5% vs 72.8% for Cohort A vs B (P = .48).

Among randomized participants (n = 516), the median age was 60 years, with 79% of the study population being male and 92% being White. Stratification by induction regimen revealed that 73% received intensive therapy, such as high-dose cytarabine, and 27% received nonintensive regimens. BTK inhibitors were rarely used during induction (7.2%) or maintenance (0.3%).

Causes of death in the study included lymphoma progression (4.7% in Cohort A; 3.5% in Cohort B), COVID-19 (5.1% vs. 6.6%), and other causes (5.0% vs. 4.6%).

“[These data] could be practice changing because if there is a subgroup that may still benefit from transplant that we can identify with MRD testing. It may be important to identify those patients, and at the same time, we can spare the majority,” Fenske said in the question-and-answer portion of the presentation. “Of the patients who we tested for MRD, over 70% were MRD negative, so if we can safely spare those patients the potential toxicities of transplant, I think that’s a big step forward. Historically, somewhere in the range of 1% to 2% of patients actually die from complications from transplant, and others will experience significant toxicities and effects on their quality of life. If we can spare patients from going through all of that, I think that alone will be a big step forward.”

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REFERENCE
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. Presented at: ASH 2024 Annual Meeting. December 7-10, 2024; San Diego, CA. Abstract LBA-6