Addition of Tocilizumab to Cyclosporine-a/ Mycophenolate Mofetil (CSA/ MMF) Graft-Vs-Host Disease (GVHD) Prophylaxis Significantly Abrogates Pre-Engraftment Syndrome (PES) & Severe Acute Gvhd after Adult Double Unit Cord Blood Transplantation (dCBT)
Year: 2020
Type: article
Abstract: Background Anti-thymocyte globulin-free dCBT is associated with high rates of acute GVHD (aGVHD) especially involving the GI tract. Investigation of augmented aGVHD prophylaxis is indicated. Methods We are investigating the addition of a single dose of tocilizumab 8 mg/kg (day -1) to CSA/ MMF (starting day -3) aGVHD prophylaxis in adult patients (pts) with hematologic malignancies undergoing dCBT with intermediate intensity Cy 50/ Flu 150/ Thio 10/ TBI 400 conditioning (NCT03434730). Outcomes of the first 26 patients (with survivor follow-up of at least 100 days) were analyzed & compared to 54 dCBT historic controls transplanted with identical conditioning & only CSA/ MMF. All patients received letermovir if CMV seropositive. Results 26 pts [median age 47 years (range 26-60), median weight 82 kg (range 59-125), 11 AML, 8 ALL, 2 MPAL, 3 MDS/ CML, 2 NHL, median age-adjusted HCT-CI 2.5 (range 0-6)] received dCB grafts with a median CD34+ cell dose of 1.5 × 10 5 /kg/unit (range 0.23-5.94) & median unit-recipient 8-allele HLA-match of 5/8 (range 3-6). One patient had graft failure in the setting of low graft viability/ disseminated adenovirus & a second pt had early transplant-related mortality (TRM) with incomplete count recovery. The remaining 24 patients engrafted at a median of 24 days (range 18-40) for a cumulative incidence of 92% (95%CI:67-98). 88% (95%CI:59-97) of pts engrafted platelets at a median of 43 days (range 32-78). Of evaluable pts, 68% & 83% had 100% single-unit donor chimerism in the blood at days 30 & 100, respectively; single-unit dominance was observed in the remaining cases. Six of 26 pts (23%) developed pre-engraftment syndrome (PES) at a median of 12.5 days, & only 3 of these (12%) required systemic corticosteroids. Additionally, 16 pts (62%) had no neutropenic fever prior to engraftment. The day 100 cumulative incidence of grade II-III & grade III aGVHD was 62% (95%CI:39-78) & 4% (95%CI:<1-17), respectively (Figure). While 16 pts developed upper GI aGVHD, 6 had stage 0+ (stool volume < 500 cc) lower GI aGVHD & the incidence of more severe lower GI involvement was very low [stage 1 (n = 2), stage 3 (n = 1) & no stage 4]. With a median survivor follow-up of 314 days, 1-year overall survival (OS) is 77% (95%:61-98). Five of 26 patients have died to date (1 graft failure, 2 organ failure, 2 infection) with no GVHD-associated TRM. Comparison with historic controls (Table) showed tocilizumab-based dCBT is associated with similar engraftment, reduced PES, reduced severe aGVHD & similar OS to CSA/ MMF alone dCBT. Conclusions Tocilizumab-based dCBT appears safe with reduced PES & grade III-IV aGVHD. While many pts developed upper GI aGVHD, the marked reduction in lower GI aGVHD supports preferential reduction of T-cell homing to the lower gut. Investigation of this approach including aGVHD treatment responses, immune recovery & correlative biomarker/ microbiota studies are ongoing.
Authors: Ioannis Politikos, Molly A. Maloy, Sean M. Devlin, Kristine Naputo, Valkal Bhatt, Kelcey Skinner, Christina Cho, Parastoo B. Dahi, Sergio A. Giralt, Boglarka Gyurkocza, Alan M. Hanash, Ann A. Jakubowski, Esperanza B. Papadopoulos, Miguel Perales, Jonathan U. Peled, Craig S. Sauter, Michael Scordo, Gunjan L. Shah, Roni Tamari, Doris M. Ponce, Juliet N. Barker
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W3001086244