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Clinical Trial
. 2025 May 27;9(10):2570-2584.
doi: 10.1182/bloodadvances.2024014177.

Phase 2 trial of cyclosporine-A, mycophenolate mofetil, and tocilizumab GVHD prophylaxis in cord blood transplantation

Ioannis Politikos  1   2 , Samantha Brown  3 , Joshua A Fein  2 , Stephen Eng  1 , Kristian Casem  1 , Stephanie Chinapen  1 , Sean Quach  1 , Andromachi Scaradavou  4   5 , Christina Cho  6 , Parastoo Dahi  1   2 , Sergio A Giralt  1   2 , Boglarka Gyurkocza  1   2 , Alan M Hanash  1   2 , Ann A Jakubowski  1   2 , Esperanza B Papadopoulos  1   2 , Miguel-Angel Perales  1   2 , Doris M Ponce  1   2 , Brian C Shaffer  1   2 , Roni Tamari  1   2 , James W Young  1   2 , Sean Devlin  3 , Jonathan U Peled  1   2 , Juliet N Barker  2
Affiliations
Clinical Trial

Phase 2 trial of cyclosporine-A, mycophenolate mofetil, and tocilizumab GVHD prophylaxis in cord blood transplantation

Ioannis Politikos et al. Blood Adv. .

Abstract

Double-unit cord blood transplantation (dCBT) has been associated with high rates of progression-free survival (PFS) in adults with hematologic malignancies but also with relatively high rates of acute graft-versus-host disease (aGVHD). We conducted a single-arm, phase 2 clinical trial that investigated the addition of tocilizumab, an interleukin-6 receptor blocker, to cyclosporine-A (CSA) and mycophenolate mofetil (MMF) for aGVHD prophylaxis after intermediate-intensity dCBT. A total of 45 patients (median age, 47 years; range, 27-60 years; 80% acute leukemia; median hematopoietic cell transplant-comorbidity index, 2) were enrolled from March 2018 to March 2021. Transplant outcomes were compared with 39 previous CSA and MMF dCBT controls with similar inclusion criteria. Tocilizumab recipients had less pre-engraftment syndrome (38%; 95% confidence interval [CI], 24-52 vs 72%; 95% CI, 54-84; P < .001) but inferior day 45 neutrophil engraftment (93%; median, 25.5 days vs 97%; median, 22 days; P = .009]. The primary end point of day 100 grade 2 to 4 aGVHD was no different between groups (71%; 95% CI, 55-82 with tocilizumab vs 82%; 95% CI, 65-91; P = .11). However, there was a trend toward a lower day 100 incidence of stage 1 to 4 lower gastrointestinal aGVHD with tocilizumab (16%; 95% CI, 7-28 vs 33%; 95% CI, 19-48; P = .059). There were no significant differences in the 3-year incidences of relapse, transplant-related mortality, PFS, or overall survival between the groups. Tocilizumab recipients exhibited a distinct pattern of gut microbiome disruption. In summary, tocilizumab-based GVHD prophylaxis delayed neutrophil recovery without a significant reduction in aGVHD and had no survival benefit after dCBT. Investigation of alternative strategies to prevent severe aGVHD after dCBT is warranted. This trial was registered at www.clinicaltrials.gov as #NCT03434730.

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Conflict of interest statement

Conflict-of-interest disclosure: I.P. reports receiving research funding from Merck; honoraria from PRECISIONheor; and serving on a data and safety monitoring board (DSMB) for ExCellThera. A.S. reports serving as a consultant on the scientific advisory board of ExCellThera. S.A.G. reports serving as a consultant for and receiving honoraria and research funding from Celgene and Novartis; serving as a consultant for and receiving research funding from Amgen, Actinuum, and Miltenyi Biotech; serving as a consultant for and receiving honoraria from Jazz Pharmaceuticals and Omeros; receiving research funding from Takeda; and serving as a consultant for Kite Pharma. B.G. reports receiving research funding from Actinium Pharmaceuticals and serving on the DSMB for Synthetic Biologics, Inc. M.A.P. reports receiving honoraria from Adicet, Allogene, AlloVir, Caribou Biosciences, Celgene, Bristol Myers Squibb, Equilium, Exevir, ImmPACT Bio, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Sanofi, Syncopation, VectivBio AG, and Vor Biopharma; serving on DSMBs for Cidara Therapeutics and Sellas Life Sciences; serving on on the scientific advisory board of NexImmune; reports ownership interests in NexImmune, Omeros, and OrcaBio; and reports institutional research support for clinical trials from Allogene, Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis. D.M.P. reports serving as a consultant for Kadmon/Sanofi Corporation, CareDx, Incyte, and Ceramedix, and receiving research funding from Incyte. B.C.S. reports receiving consulting fees from Hansa Biopharma and Gamida Cell. R.T. reports serving as a Blood and Marrow Transplant Clinical Trials Network medical monitor for Angiocrine Bioscience and Omeros. J.W.Y. reports owning equity in Merck, Pfizer, and Amgen. J.U.P. reports receiving research funding, intellectual property fees, and travel reimbursement from Seres Therapeutics and consulting fees from DaVolterra, CSL Behring, Crestone Inc, and from MaaT Pharma. He reports serving on an advisory board of and holding equity in Postbiotics Plus Research and Prodigy Biosciences. He further reports filing intellectual property applications related to the microbiome (reference numbers #62/843,849, #62/977,908, and #15/756,845). Memorial Sloan Kettering Cancer Center has financial interests relative to Seres Therapeutics. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Neutrophil recovery in Toci and No Toci patients. The cumulative incidence of neutrophil recovery was 93% (95% CI, 79-98) in the Toci patient group (median day, 25.5) vs 97% (95% CI, 72-100) in the No Toci patient group (median, 22 days); P = .009.
Figure 2.
Figure 2.
PES and aGVHD in the Toci and No Toci patient groups. (A) The cumulative incidence of PES was of 38% (95% CI, 24-52) in the Toci group vs 72% (95% CI, 54-84) in the No Toci group (P < .001). (B) The cumulative incidence of grade 2 to 4 aGVHD was 71% (95% CI, 55-82) in the Toci group vs 82% (95% CI, 65-91) in the No Toci group (P = .11). (C) The cumulative incidence of grade 3 to 4 aGVHD was 11% (95% CI, 4-22) in the Toci group vs 23% (95% CI, 11-37) in the No Toci group (P = .13). (D) The cumulative incidence of stage 1 to 4 lower GI GVHD by day 100 was 16% (95% CI, 7-28) in the Toci group vs 33% (95% CI, 19-48) in the No Toci group (P = .059).
Figure 3.
Figure 3.
Survival outcomes in the Toci and No Toci groups. There were no significant differences in TRM (A), relapse (B), PFS (C), or OS (D) between the Toci and No Toci patients.
Figure 4.
Figure 4.
Comparison of immune reconstitution between the Toci and No Toci groups. Tocilizumab did not adversely impact immune subset recovery.
Figure 4.
Figure 4.
Comparison of immune reconstitution between the Toci and No Toci groups. Tocilizumab did not adversely impact immune subset recovery.
Figure 5.
Figure 5.
Tocilizumab-based GVHD prophylaxis is associated with lower Enterococcus abundance. (A) The alpha diversity, as measured by the Inverse Simpson index, is shown over time relative to transplant day. Both the Toci and No Toci groups exhibited a similar decrease in diversity over the first 2 weeks following infusion. No difference was observed in diversity between groups when compared using the Wilcoxon test for 5-day intervals. (B) The relative abundance of Enterococcus over time was markedly different between the Toci and No Toci cohorts (multivariable linear mixed-effects regression P = .0056). (B) Principal component plots are shown; 4 clusters were identified when using k-means clustering (top left). Toci exposure (top-right), antibacterial exposure within previous 4 days (bottom left), and most prevalent genus in each sample (bottom right) are shown. The Toci vs No Toci contribution to the clusters was significantly different (Kruskal-Wallis; P = 1.3e-14). Antibiotics to which patients were exposed in the 4 days before each sample collection were classified by their extent of anticipated perturbation of human intestinal microbiome communities as previously described.
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References

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