Adding CD117 Antibody to Alemtuzumab, Low Dose Total Body Irradiation (TBI), and Sirolimus for Matched Related Donor (MRD) Hematopoietic Cell Transplant (HCT) in Sickle Cell Disease (SCD): Initial Results

Non-myeloablative (NMA) conditioning is increasingly adapted with success in MRD and alternative donor HCT in individuals with SCD. Briquilimab is an unconjugated monoclonal antibody (mAb) that targets human CD117 (c-kit receptor) with high affinity and blocks the binding of stem cell factor (SCF). SCF signaling through CD117 is one essential pathway for the survival, maintenance, and proliferation of HSC. We hypothesized that adding briquilimab to low dose TBI would have a synergistic effect in clearing host HSC from their bone marrow niche, and intensify a low dose TBI HCT regimen without cytotoxic chemotherapy.

13 patients with homozygous sickle (HbSS) and 1 patient with sickle-beta 0 thalassemia (age range 5-34 years) received briquilimab 0.6 mg/kg on day -11, alemtuzumab 1.0 mg/kg divided over day -7 through -3, 300 cGy TBI on day -2, sirolimus to target trough level of 10 ng/mL starting on day -1, and unmanipulated filgrastim mobilized peripheral blood stem cells on day 0 (10.8-20.4 x 10e6 CD34 cells/kg and 1.9-7.5 x 10e8 CD3 cells/kg). Donors were all HLA-matched. The main indication for HCT was frequent vaso-occlusive episodes; other indications include acute chest syndrome, elevated estimated right heart pressure by echo (TRV >2.5 m/s), sickle liver disease with iron overload, and polyarticular avascular necrosis.

Briquilimab levels were available for 13 patients and its clearance was similar between patients: the mean concentration at one day after infusion (day -10) was 6040 ng/mL (range 2635-8749); ten days after infusion (day -1), 677 (21-1481). 4 patients had grade 1 reaction possibly related to briquilimab: two with headache, one with acne-like rash, and one with fever. All patients had briquilimab level below the 1500 ng/mL threshold to proceed with HSC infusion as scheduled. Lymphocyte counts decreased to undetectable levels after 2-3 doses of alemtuzumab. Reticulocyte counts reached nadir at median of day 8 (1-17). All patients engrafted: neutrophil recovered >500 cells/uL on median of day 13 (range 12-17); platelet >50 cells/uL, day 17 (5-26). HCT related complications included one patient with PRES, one required CMV treatment, one with grade 2 upper GI GVHD (resolved without treatment), and two with graft failure (day 95 and 105; both had autologous recovery). All patients are alive with a median follow-up of 195 days (range 94-564).

13 patients have reached day 100 post HCT time point. Omitting the two patients with graft failure, their median donor chimerism was 100% (94-100) in myeloid and 7% (0-64) in CD3+ cells. 10 patients (8 engrafted) have reached 6 months post HCT, median myeloid chimerism was 99.5% (66-100), CD3 35% (0-66). 3 patients have reached 1 year post HCT, their myeloid/CD3 chimerism were 98%/55%, 100%/86%, and 100%/74%; these three patients have discontinued immunosuppression.

Compared to our prior alemtuzumab/300 cGy TBI regimen, several observations can be made. There were no additional toxicities or increased rates of viral reactivation or GVHD. Preliminary descriptive analyses of donor chimerism showed at day 100, 10 of 11 engrafted patients (91%) had ≥98% donor myeloid. The associated 95% lower confidence bound = 63.6%, a figure higher than the 62% of participants observed with ≥98% donor myeloid in the prior protocol. Donor CD3 chimerism ranged from 0-66%, similar to the prior protocol. Graft failure rate was 15% (2 of 13), also similar to the prior rate of 13%.

Overall, addition of briquilimab to our NMA regimen was well tolerated. Although there were no major differences in the usual HCT outcomes, there was a signal that more patients had full myeloid chimerism (≥98%) at earlier time points. Longer follow-up is needed to detail the trajectory of myeloid and CD3 chimerism. Strategies to increase myeloid and CD3 chimerism are warranted.