Individualized anti-thymocyte globulin dosing improves immune reconstitution after HSCT
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ORLANDO — Individualized dosing of rabbit anti-thymocyte globulin significantly improved CD4-positive T-cell recovery after allogeneic hematopoietic stem cell transplantation among children, according to results of the open-label phase 2 PARACHUTE study presented at TCT | Transplantation & Cellular Therapy Meetings.
Despite the change in dosing, the treatment maintained a strong anti-graft-versus-host disease effect, results showed.
“The challenges in stem cell transplants include reducing toxicity and [improving] disease control in terms of relapse,” Rick Admiraal, MD, PhD, clinical pharmacologist and postdoctoral researcher in pediatrics at Princess Máxima Center for Pediatric Oncology in the Netherlands, said during his presentation. “Adequate and predictable T-cell reconstitution plays an important role in this.”
Anti-thymocyte globulin (Thymoglobulin, Genzyme), or ATG, is used during allogeneic HSCT to prevent GVHD and graft failure. However, the treatment is associated with unpredictable toxicity and poor immune reconstitution, which can lead to relapse, viral reactivations and higher mortality.
Previous studies have shown that early CD4-positive T-cell reconstitution, occurring within 100 days, is associated with improved survival.
Admiraal and colleagues sought to evaluate whether individualized ATG dosing regimens would improve CD4-positive T-cell recovery, without increasing the incidence of GVHD, compared with historical fixed-dosing methods.
The analysis included data of 58 children (mean age at transplant, 7.7 years; range, 0.2-17.8; 50% male) — 19 of whom were treated during a stage I safety phase and 39 during a stage II efficacy stage — who received individualized ATG dosing based on results of a previously validated population pharmacokinetic and pharmacodynamic model. Cumulative doses of ATG — initiated 9 days prior to transplant — ranged from 2 mg/kg to 10 mg/kg according to weight, baseline recipient lymphocyte counts and stem cell source.
Researchers compared results of these patients with a historical cohort of 100 children (mean age at transplant, 7.5 years; range, 0.2-19.4; 59% male) who received a fixed cumulative ATG dose of 10 mg/kg starting 5 days prior to transplant.
Successful CD4-positive T-cell reconstitution — defined as CD4-positive T-cell counts greater than 50 CD4/mm3 at two consecutive time points within 100 days after transplant in patients alive without relapse or graft failure — served as the study’s primary endpoint. Secondary endpoints included OS, EFS, and incidence of GVHD and graft failure.
Minimal follow-up was 1 year.
Results showed a superior CD4-positive T-cell reconstitution rate in the individualized dosing group compared with the historical group (83% vs. 54%; HR = 2.4; 95% CI, 1.6-3.6).
Additionally, the individualized group showed a trend toward improved OS (81% vs. 66%; HR = 0.54; 95% CI, 0.27-1.07) and EFS (79% vs. 61%; HR = 0.52; 95% CI, 0.27-1.01) compared with the historical group. A greater proportion of patients who received fixed ATG dosing experienced relapse- and therapy-related mortality (26% ± 7% vs. 11% ± 8%), but the difference did not reach statistical significance.
Researchers observed no differences in incidence of grade 3 to grade 4 acute GVHD (7% ± 3% for both groups), moderate to severe chronic GVHD (4% ± 3% vs. 10% ± 3%) and graft failure (4% ± 2% vs. 5% ± 2%) between the individualized- and fixed-dosing groups.
“An individualized rabbit ATG dosing nomogram is feasible in pediatric HSCT and [induces] a major improvement in early T-cell reconstitution,” Admiraal said. “This is a simple and new approach to improve outcomes of HSCT.” – by John DeRosier
Reference:
Admiraal R, et al. Abstract 41. Presented at: TCT | Transplantation & Cellular Therapy Meetings; Feb. 19-23, 2020; Orlando.
Disclosures: Admiraal reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
Back to TopMaria Teresa Lupo-Stanghellini, MD
We had been providing a fixed dose of ATG to everyone, but now we are moving toward a tailored strategy that is still effective for GVHD control. This is one of the first studies addressing this issue. We are reducing the dose at different levels for each patient.
We will be able to translate this approach to the adult population. There are major weight variations among adults. Despite this, the standard is a 5 mg/kg or 10 mg/kg dose. These data suggest that we need to be more aware of the pharmacokinetics and the lymphocyte burden, which is what is being depleted with HSCT. The researchers have created a formula that will hopefully make it safer.
ATG has been around for 35 to 40 years, and there is still controversy over its use. There’s too much toxicity and too much relapse, but we’ve only been using it one way. Sometimes we have to step back, think out of the box and try something new.
Further, this approach is very simple. It’s not a difficult calculation and it is not time-consuming.
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