Combination of Post-Transplant Cyclophosphamide and Everolimus in Resistant Lymphomas

Overview

This retrospective study of 33 patients with relapsed/refractory aggressive T- and B-cell lymphomas undergoing allogeneic hematopoietic stem cell transplantation (aHSCT) demonstrated that the combination of post-transplant cyclophosphamide (PTCy) and everolimus provides effective graft-versus-host disease (GvHD) prophylaxis with favorable survival outcomes. The regimen resulted in manageable acute and chronic GvHD rates, a 2-year overall survival (OS) of 64%, progression-free survival (PFS) of 55%, and a graft-versus-host disease-relapse-free survival (GRFS) of 48%. Non-relapse mortality (NRM) remained a challenge, primarily due to infectious complications.

Background

Aggressive lymphomas often require curative approaches including immunochemotherapy, CAR-T cell therapy, and allogeneic hematopoietic stem cell transplantation (aHSCT) for refractory cases. Graft-versus-host disease (GvHD) is a significant complication post-aHSCT, contributing to morbidity and mortality. Traditional calcineurin inhibitor-based immunosuppression has limitations including toxicity and incomplete GvHD prevention. Post-transplant cyclophosphamide (PTCy) preserves regulatory T cells and has shown promise in GvHD prophylaxis, while everolimus offers immunosuppressive, anti-neoplastic, and anti-viral effects with less nephrotoxicity. Combining PTCy with everolimus aims to improve GvHD control and survival in resistant lymphoma patients.

Data Highlights

Key Findings

• All patients achieved donor engraftment with median neutrophil and platelet recovery times of 17 and 21 days, respectively.
• Acute GvHD occurred in 63.6% of patients, mostly grade II; severe grade III-IV aGvHD was low (12.2%).
• Chronic GvHD developed in 21.2% with only 9.1% requiring ongoing systemic immunosuppression.
• Median progression-free and overall survival were not reached; 2-year OS was 64% and PFS 55%.
• Relapse occurred in 20% by 2 years, with a median time to relapse of 4 months.
• Non-relapse mortality was 24.2% at 2 years, mainly due to infections including COVID-19 complications.

Clinical Implications

The combination of PTCy and everolimus is a viable GvHD prophylaxis strategy in patients with resistant aggressive lymphomas undergoing aHSCT, offering effective GvHD control with acceptable toxicity and encouraging survival outcomes. Clinicians should remain vigilant for infectious complications contributing to non-relapse mortality and consider supportive measures accordingly. This regimen may provide an alternative to calcineurin inhibitor-based protocols, especially in patients at risk for nephrotoxicity.

Conclusion

PTCy combined with everolimus demonstrates promising efficacy and safety in preventing GvHD in refractory lymphoma patients undergoing aHSCT, achieving favorable survival and GvHD-relapse-free outcomes. Further prospective studies are warranted to confirm these findings and optimize supportive care to reduce infectious mortality.

References

1. OCTET-EVER Trial Results -- Everolimus and PTCy in GvHD Prophylaxis
2. Hovon-96 Trial -- PTCy with CsA vs CsA with Mycophenolic Acid
3. Bolaños-Meade et al. Phase 3 Trial -- PTCy Backbone Immunosuppression
4. Solomon et al. Phase 2 Trial -- PTCy and Sirolimus in Hematologic Malignancies