Advancing Care in Older Adult T-Cell Leukemia/Lymphoma: Phase 2 Trial of Moga-CHOP-14 Combination Therapy

Highlight

1. Moga-CHOP-14, a regimen combining anti-CCR4 antibody mogamulizumab with the CHOP chemotherapy backbone, significantly improves 1-year progression-free survival (PFS) in older patients with untreated aggressive adult T-cell leukemia/lymphoma (ATL).
2. The complete response (CR) rate reached 64.6%, while overall response rate (ORR) was 91.7%, indicating robust antitumor activity.
3. Patients harboring CCR4 mutations and those experiencing mogamulizumab-associated cutaneous adverse events (cAEs) showed better overall survival (OS), suggesting possible predictive biomarkers.
4. The regimen was well tolerated with no unexpected toxicities, supporting its feasibility in an older, transplant-ineligible population.

Study Background and Disease Burden

Adult T-cell leukemia/lymphoma (ATL) is a rare, aggressive peripheral T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Despite its poor prognosis, especially in aggressive subtypes, there is no standard first-line treatment established for older patients or those ineligible for stem cell transplantation. The conventional CHOP chemotherapy regime (cyclophosphamide, doxorubicin, vincristine, and prednisolone) has demonstrated limited efficacy in ATL, with frequent relapses and suboptimal survival outcomes. Meanwhile, mogamulizumab, a humanized monoclonal antibody targeting CC chemokine receptor 4 (CCR4)—frequently expressed in ATL cells—has shown promising antitumor effects and synergy with chemotherapy. The integration of mogamulizumab with CHOP chemotherapy (Moga-CHOP) has the potential to address the unmet need for effective, tolerable therapies for older patients with ATL.

Study Design

This was a multicenter, open-label, phase 2 trial enrolling treatment-naïve patients aged 66 years or older, as well as patients aged 56 to 65 years who were ineligible for transplantation, all diagnosed with aggressive ATL. The treatment protocol consisted of six cycles of Moga-CHOP administered every 14 days (CHOP-14), followed by two cycles of mogamulizumab monotherapy. Per protocol amendment, dosing intervals could be extended to 21 days at physician discretion based on patient tolerance. The primary endpoint was 1-year progression-free survival (PFS). Secondary endpoints included complete response rate (CR), overall response rate (ORR), overall survival (OS), 1-year event-free survival (EFS), and safety profile. Additionally, the trial assessed the impact of CCR4 gene mutation status and the occurrence of mogamulizumab-associated cutaneous adverse events (cAEs) on treatment outcomes, as these factors were hypothesized to influence prognosis.

Key Findings

Among 48 evaluable patients, the 1-year PFS was 36.2% (90% confidence interval [CI], 24.9–47.6%) with a median follow-up of 1.6 years. Corresponding 1-year OS and event-free survival (EFS) were 66.0% and 29.9%, respectively. The regimen achieved a CR rate of 64.6% and an ORR of 91.7%, reflecting substantial anti-ATL activity.

Safety was acceptable relative to expectations for this population; no unexpected adverse events occurred. Notably, 42.6% of patients (20 of 47) received the full CHOP-14 regimen every two weeks, and 25.5% (12 patients) completed all six cycles of CHOP. The remaining patients had dosing intervals extended due to clinical judgment, underscoring some challenges in maintaining the 14-day cycle in older patients.

Genotypic analysis revealed that patients harboring CCR4 mutations and those who developed mogamulizumab-associated cutaneous adverse events demonstrated improved overall survival, suggesting these as potential predictive markers for treatment response.

Despite significant improvements in PFS compared to historical controls receiving CHOP alone, the optimal scheduling interval for CHOP chemotherapy in combination with mogamulizumab remains to be clarified. Still, Moga-CHOP stands as an effective and tolerable first-line therapeutic option for this difficult-to-treat patient group.

Expert Commentary

This phase 2 study represents a meaningful advance in managing older patients with aggressive ATL, a subgroup traditionally facing poor outcomes due to limited therapeutic options and transplant ineligibility. The use of mogamulizumab to target CCR4-positive malignant T cells, combined with standard CHOP chemotherapy, leverages an important mechanistic insight with clinical benefit.

The finding that CCR4 mutation status correlates with better survival aligns with prior evidence suggesting that mutations in this receptor may augment antibody-mediated cellular cytotoxicity or represent a distinct biologic subtype responsive to targeted therapy. Furthermore, mogamulizumab-induced cutaneous adverse events may act as a surrogate marker for immune engagement, as seen in other immunotherapeutic contexts.

However, the study’s relatively small sample size and the allowance of variable chemotherapy intervals necessitate cautious interpretation and warrant validation in larger, randomized trials. Additionally, the feasibility of maintaining intense dosing in older populations deserves further exploration with supportive strategies.

In the broader context of ATL treatment, these results reinforce the utility of personalized approaches combining targeted antibodies with chemotherapy. They also prompt investigation into combining mogamulizumab with novel agents or integrating it within stem cell transplant frameworks when feasible.

Conclusion

This multicenter phase 2 trial highlights that Moga-CHOP-14 provides a significant efficacy advantage with manageable toxicity in older patients and those ineligible for transplantation with untreated aggressive ATL. Achieving a high overall response rate and 1-year PFS improvement marks an important step toward establishing a new standard of care in this vulnerable population. The association of CCR4 mutations and mogamulizumab-associated cutaneous adverse events with improved survival offers promising avenues for biomarker-driven patient selection. Nevertheless, further research is needed to define the optimal chemotherapy interval, confirm long-term benefits, and explore combination strategies to improve outcomes. Clinicians should consider Moga-CHOP as a preferable first-line therapy while balancing individual patient tolerability and clinical context.

References

Yoshimitsu M, Choi I, Kusumoto S, Shimokawa M, Utsunomiya A, Suehiro Y, et al. A phase 2 trial of CHOP with anti-CCR4 antibody mogamulizumab for older patients with adult T-cell leukemia/lymphoma. Blood. 2025 Sep 18;146(12):1440–1449. doi: 10.1182/blood.2024027902. PMID: 40373281.

Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukemia-lymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol. 1991;79(3):428-37.

Cook LB, Fuji S, Hermine O, et al. ATL International Consensus Meeting Report and Recommendation. J Clin Oncol. 2022;40(27):3048-3059.