CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 23, 2023
Expiration: March 22, 2024
Corey Cutler, MD, MPH, FRCPC:
For more than 30 years, standard prophylaxis for GVHD following allogeneic stem cell transplantation (alloSCT) has been a combination of a calcineurin inhibitor, such as tacrolimus (TAC), with methotrexate (MTX).17-19
The randomized phase II BMT CTN 1703 study was a pivotal trial performed by the Blood and Marrow Transplant Clinical Trials Network to examine a novel acute and chronic GVHD prevention strategy.20 This phase III study was based on a prior randomized phase II trial (BMT CTN 1203), which suggested that the posttransplant cyclophosphamide (PTCy) regimen was the best among novel regimens to be tested against the TAC and MTX standard, with a significant improvement in GVHD-free relapse-free survival (GRFS) when compared with a Center for International Blood and Marrow Transplant Research control cohort (HR: 0.72; P = .044).21
Corey Cutler, MD, MPH, FRCPC:
At ASH 2022, Holtan and colleagues20 presented analyses from BMT CTN 1703 that included data for 30 centers and more than 400 enrolled patients. The study accrued ahead of schedule because of the excitement to answer the question of optimal prophylaxis against GVHD. The trial included recipients of matched related and unrelated donor transplants, including those with 1 antigen mismatched unrelated donors. The primary endpoint was GRFS, which comprises grade III/IV acute GVHD, chronic GVHD requiring systemic immune suppression, any relapse, or death as a single composite endpoint, with any 1 of those events constituting failure to meet the study endpoint.
Corey Cutler, MD, MPH, FRCPC:
Baseline characteristics between the 2 groups were largely well balanced. Approximately 66% of patients had received a transplant from unrelated donors. Common conditioning regimens used were nonmyeloablative fludarabine/busulfan (approximately 26% and 28%) or fludarabine/melphalan (approximately 57% in both arms). Primary disease in both arms was acute myeloid leukemia (approximately 50% and 46%) and myelodysplastic syndromes (approximately 29% and 30%).
Corey Cutler, MD, MPH, FRCPC:
The primary endpoint was met. One-year GRFS was statistically superior in the PTCy/TAC/mycophenolate mofetil (MMF) arm compared with the TAC/MTX arm (52.7% vs 34.9%; HR: 0.641; P <.001).
The secondary endpoints also favored the experimental group. The rate of severe acute GVHD was 14.7% in the TAC/MTX arm vs only 6.3% in the PTCy/TAC/MMF arm. In addition, the rate of chronic GVHD requiring immune suppression at 1 year was 25% in the TAC/MTX arm vs only 12.5% in the PTCy/TAC/MMF arm (P = .001). However, it is expected that these rates will increase over time, and the rate of chronic GVHD is lower than seen in historical controls.21
No treatment effect was seen on relapse/progression, which is reassuring given greater immunosuppression with the PTCy/TAC/MMF vs TAC/MTX regimen. Likewise, there was no change in transplant-related mortality and no difference in overall survival or disease-free survival at 1 year, although an absolute increase of approximately 5%—which did not reach statistical significance—was seen in the experimental arm.
Corey Cutler, MD, MPH, FRCPC:
An interesting safety finding for me was an increased incidence of grade 2 infections in the experimental arm (P = .002). Rates of grade 3 infections (12.2% vs 13.3%; P = .817) and death due to infections (17% vs 18%) at 1 year were similar between treatment arms. Most infections occurred early and were predominantly viral.
Corey Cutler, MD, MPH, FRCPC:
A decrease in the rate of stable, long-term engraftment (<3% donor cells) was seen in 3.0% of patients receiving PTCy/TAC/MMF vs 0.5% of patients receiving TAC/MTX by Day 100. Secondary (late) graft failures were seen in 2.9% of patients receiving PTCy/TAC/MMF vs 0.9% of patients receiving TAC/MTX (P = .172).
Corey Cutler, MD, MPH, FRCPC:
In terms of the overall impact of this trial, little doubt remains in my mind that PTCy/TAC/MMF is the new standard in reduced-intensity transplantation from related and unrelated donors. What remains to be answered is whether the effects were the same in the related and unrelated donor arms, which carry different levels of risk for both acute and chronic GVHD.
A 1-year GRFS of only 62% is far from optimal, and continued improvement on this PTCy-based regimen is needed. Other strategies include substitution of the calcineurin inhibitor for sirolimus or yet another agent to replace mycophenolate, which most of us believe is not a very potent immunosuppressive agent. Graft manipulation strategies that might be able to further reduce the rates of both acute and chronic GVHD, as well as novel strategies to incorporate antithymocyte globulin into transplant conditioning, need to be explored, as do other strategies for the timing and dosing of PTCy.
Overall, I do believe PTCy/TAC/MMF can become a standard of care in the reduced-intensity setting now. One key consideration with this PTCy-based regimen is the need to use prophylaxis against infections because of the increased risk of grade 2 and potentially grade 3 infections, including an increased risk of viral infections, as reported in this study.
Corey Cutler, MD, MPH, FRCPC:
In the United States, grade II-IV acute GVHD occurs in 40% to 85% of pediatric patients undergoing alloSCT from an unrelated donor.22 Corticosteroids are the standard first-line therapy for treatment of acute GVHD in pediatric patients, with approximately 30% to 50% of patients responding to this treatment.23
The phase III REACH2 study evaluated ruxolitinib, a JAK1/2 inhibitor, vs best available therapy in patients aged 12 years or older with steroid-refractory acute GVHD.24 Results from REACH2 showed an improved and durable overall response rate (ORR) with ruxolitinib compared with best available therapy (62.3% vs 39.4%; P <.001). Based on the results from REACH2, in 2019 the FDA approved ruxolitinib for patients aged 12 years or older with steroid-refractory acute GVHD.25
Corey Cutler, MD, MPH, FRCPC:
The open-label, dose-finding phase I/II REACH4 study is a large prospective study evaluating ruxolitinib plus corticosteroids and a calcineurin inhibitor in pediatric patients (aged 28 days to 18 years) with either treatment-naive or steroid-refractory grade II-IV acute GVHD following alloSCT.26 This study is an attempt to prospectively determine response rates in a pediatric patient population including those with previously untreated disease.
The primary endpoints for the phase I portion of the study were pharmacokinetic parameters and determination of the recommended phase II dose. Based on safety, tolerability, and pharmacokinetics, the phase II dose was found to be 10 mg twice daily in children aged 12-17 years (group 1), which is the same dose that is approved in adults. For children aged 6-11 years (group 2), 5 mg twice daily was recommended, and for children aged 2-5 years (group 3), 4 mg/m2 twice daily was recommended. The primary endpoint for the phase II portion was ORR at Day 28.
Corey Cutler, MD, MPH, FRCPC:
Across the 3 age groups, 45 patients were treated in the ruxolitinib arm, of whom approximately 70% were steroid refractory and 30% were treatment naive. In addition, 60% to 67% of these patients had grade II disease, 0% to 9% had grade IV disease, and the remaining 20% to 33% had grade III disease.
Corey Cutler, MD, MPH, FRCPC:
Overall, 45 patients were treated with ruxolitinib, approximately 49% completed the 24-week treatment period, and approximately 67% entered long-term follow-up (up to 2 years).
The most common reasons for ruxolitinib discontinuation included lack of efficacy (26%) and AEs (22%).
Corey Cutler, MD, MPH, FRCPC:
Overall, the ORR at Day 28 was very impressive at 84% (90% CI: 77.2%-92.5%). Approximately 50% of patients achieved a complete response (CR), and 35% had a partial response (PR).
In the treatment-naive group (n = 13), the ORR was slightly lower at 70%, with complete CRs seen in 53.8% of patients. By contrast, in the steroid-refractory group (n = 32), the ORR was 91%, and the CR rate was approximately 47%. The mechanism of this reversed response rate remains to be elucidated.
The durability of ruxolitinib responses was similar to that seen in adults.24 By Day 56, the ORR had been reduced to 66% in the overall population. Of note, the CR rate was the same at Day 28 and Day 56 (approximately 49%). That is due to a combination of some patients with PR transitioning to a CR but some patients with CR losing their overall response.
The overall durability of response by Day 56 was 69% for patients with steroid-refractory disease and approximately 62% for patients with treatment-naive disease.
Corey Cutler, MD, MPH, FRCPC:
In terms of safety and tolerability, the vast majority of patients (84%) had at least 1 ruxolitinib dose change or dose interruption. Toxicity was a common reason for dose change or interruption (51%). Approximately 44% and 31% of patients had to undergo dose tapering and dose change/interruption, respectively. This is not unexpected in a dose-finding study.
Corey Cutler, MD, MPH, FRCPC:
The investigators from REACH4 concluded that ruxolitinib has a comparable efficacy and safety profile in pediatric patients with steroid-refractory acute GVHD, as previously reported for REACH2.24
Based on these data, I think we now can say that ruxolitinib is effective and safe in pediatric patients with steroid refractory acute GVHD and, to a lesser degree, pediatric patients with steroid naive acute GVHD.
Corey Cutler, MD, MPH, FRCPC:
Other abstracts of interest presented at ASH 2022 examined ruxolitinib in the adult patient population, including a trial for steroid-refractory, sclerotic, chronic GVHD, which demonstrated a response rate of 47% in a hard-to-treat patient group,27 and a second trial of ruxolitinib for acute GVHD in adults treated in the first-line setting in a randomized fashion, where the response rate was 93% vs 71% in the control group.28
A highly anticipated study for another JAK inhibitor presented at ASH 2022 was the phase II/III GRAVITAS 309 trial of various doses of itacitinib plus corticosteroids in patients with previously untreated chronic GVHD. Unfortunately, this trial failed to demonstrate an improvement in chronic GVHD responses for itacitinib plus corticosteroids when used as frontline therapy, so it will be terminated.29 Equally important was the itacitinib monotherapy trial for treatment of newly diagnosed, very low risk acute GVHD, which suggested that itacitinib was both safe and effective in this patient population, although it is currently not approved for clinical use in this setting.30
Back
