Large Clonal Hematopoiesis Clones Are Associated With Worse Survival Outcomes in MCL

Mantle cell lymphoma | Image Credit:
© Tatiana Shepeleva – stock.adobe.com

The presence of large clones of clonal hematopoiesis was associated with worse progression-free survival (PFS) and overall survival (OS) in patients with treatment-naive mantle cell lymphoma (MCL) who received maintenance therapy with lenalidomide (Revlimid) or observation following chemoimmunotherapy and autologous stem cell transplantation (ASCT), according to data from an analysis of the phase 3 MCL0208 trial (NCT02354313) published in Blood Advances.¹

At a median follow-up of 7 years, patients with large clonal hematopoiesis clones (variant allele frequency [VAF] ≥ 10%; n = 8) experienced higher risk of disease progression (HR, 2.93; 95% CI, 1.36-6.31; P = .006) and death (HR, 3.02; 95% CI, 1.21-7.55; P = .018) compared with those without myeloid clonal hematopoiesis (n = 220). Additionally, patients with large clones experienced a longer time to hematological recovery following ASCT vs those with small (VAF < 10%; n = 26) or no clones (P = .026).

“[Our data] showed for the first time that large clonal hematopoiesis clones might associate with unfavorable clinical impact in patients with MCL,” the study authors wrote.

MCL0208 Study Design

MCL0208 was an open-label, multicenter, Italian study that enrolled previously untreated patients with MCL. Patients were 18 to 65 years old and did not have clinically significant comorbidities.

All patients received 3 cycles of R-CHOP21 (rituximab cyclophosphamide, doxorubicin, vincristine, prednisone) followed by 4 g/m² of cyclophosphamide, 2 cycles of cytarabine at 2 g/m² every 3 hours for 3 days, and ASCT conditioning via BEAM (carmustine, etoposide, cytarabine, melphalan) or FEAM (fotemustine, etoposide, cytarabine, melphalan). Following ASCT, patients who experienced overall hematological recovery and a complete or partial response were randomly assigned to receive maintenance lenalidomide at 15 mg on days 1 to 21 every 28 days or observation, both over 24 months.

The primary end point was PFS.² Secondary end points included OS, disease-free survival, event-free survival, complete response (CR) rate, overall response rate, safety, and quality of life.

For the analysis, the study authors collected unsorted bone marrow and peripheral blood samples at baseline and within 12 months following ASCT.¹ The samples were then evaluated for myeloid clonal hematopoiesis via next-generation sequencing.

At baseline, the median age in the overall analysis population was 57 years (range, 32-66), and 78% of patients were male. Most patients had classic histology (92%), a Ki67 index of less than 30 (71%), lactate dehydrogenase levels at or below the upper limit of normal (70%), Mantle Cell Lymphoma International Prognostic Index (MIPI) low-risk disease (62%), and an ECOG performance status of 0 (77%). Ninety-four percent of patients had stage IV disease.

Half of the patients were randomly assigned to the lenalidomide arm (52%) and underwent random assignment following ASCT (72%). Among patients who received ASCT (n = 222), 91% experienced a CR following ASCT.

Additional Efficacy Data

Additional findings from the study showed that the presence of any myeloid clonal hematopoiesis did not significantly affect PFS (P = .457) or OS (P = .514). However, patients with large clones still displayed shortened PFS (HR, 2.27; 95% CI, 1.03-5.01; P = .042) and a trend towards worse OS (HR, 1.87; 95% CI, 0.71-4.87; P = .203) compared with those without myeloid clonal hematopoiesis after the study authors applied propensity score adjustment for age, sex, MIPI score, Ki67, bulky disease, bone marrow involvement, and blastoid subtype.

“Taken together, our findings offer novel insights in MCL biology by dynamically characterizing the myeloid clonal hematopoiesis landscape in these patients,” the study authors concluded. “We propose that large myeloid clonal hematopoiesis clones may exert a not-negligible role in lymphoma progression, potentially affecting patient outcome. Further efforts are required to elucidate how myeloid clonal hematopoiesis might influence the tumor microenvironment and eventually affect the survival of MCL cells and their response to treatment.”

References

1. Ragaini S, Galli A, Genuardi E, et al. Large clones of clonal hematopoiesis affect outcome in mantle cell lymphoma: results from the FIL MCL0208 clinical trial. Blood Adv. 2025;9(8):1805-1815. doi:10.1182/bloodadvances.2024014948
2. Phase III, randomized trial: lenalidomide vs observation after induction with rituximab followed by Cht and ASCT in MCL adult patients (MCL0208). ClinicalTrials.gov. Updated February 9, 2018. Accessed May 9, 2025. https://clinicaltrials.gov/study/NCT02354313