A phase III study of calcineurin inhibitor-free chronic GvHD prophylaxis in patients undergoing HLA-matched myeloablative HSCT

The standard approach to prevent graft-versus-host disease (GvHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) is the use of a combination therapy including calcineurin inhibitors (CNIs).¹ However, CNIs need regular pharmacokinetic monitoring, may increase the risk of renal toxicity and thrombotic microangiopathy, and their prolonged use may predispose patients to infections and reduce graft-versus-tumor effects, ultimately precluding the effectiveness of post-HSCT therapies. Chronic GvHD (cGvHD) is common post HSCT, affecting 35–55% of transplantation survivors, with higher rates and severity in peripheral blood stem cell (PBSC) compared with bone marrow (BM) grafts. More recently, CNI-free approaches using donor T-cell depletion of PBSC grafts with an intensified myeloablative conditioning regimen or in vivo post-transplantation cyclophosphamide (PTCy) as a single agent have shown promising results for GvHD prophylaxis.¹

Here, we summarize the key findings published by Luznik et al.¹ in Journal of Clinical Oncology of a phase III trial (NCT02345850) comparing CD34⁺ selected PBSCs, PTCy after a BM graft, or tacrolimus (Tac) + methotrexate (MTX) after a BM graft in patients with acute myeloid leukemia or myelodysplastic syndromes with a human leukocyte antigen (HLA)-matched donor.

Study design

This was a three-arm, phase III, multicenter, open-labelled, randomized controlled study performed by the Blood and Marrow Transplant Clinical Trial Network (BMT-CTN). The study compared HSCT approaches among patients aged ≤65 years undergoing HLA-matched myeloablative HSCT for acute leukemia in complete remission, complete remission with incomplete hematologic recovery, or myelodysplastic syndromes with <5% blasts in the BM. Patients were enrolled from 26 centers across Germany and the USA. HLA-matched related or unrelated donors were defined as 8 out of 8 matches. Patients were randomly allocated to one of the three treatment arms (Figures 1 and 2).

Figure 1. Treatment allocation*

BM, bone marrow; Cy, cyclophosphamide; GCSF, granulocyte colony stimulating factor; HSCT, hematopoietic stem cell transplantation; IV, intravenous; MTX, methotrexate; PBSC, peripheral blood stell cell; Tac, tacrolimus.

*Data from Luznik et al.¹

Figure 2. Consort diagram*

MTX, methotrexate; PTCy, post-transplantation cyclophosphamide; Tac, tacrolimus.

*Adapted from Luznik et al.¹

^†Excluding patients who withdrew from the study, died, or were lost to follow up.

The primary endpoint was a composite of moderate to severe cGvHD, disease relapse, and chronic relapse-free survival (CRFS). Secondary endpoints included overall survival (OS), acute GvHD (aGvHD), cGvHD, disease relapse, relapse-free survival, transplant-related mortality (TRM), immunosuppression-free survival, hematologic recovery, toxicities, infections, and health-related quality of life.

The primary analysis was performed using the intent-to-treat population, with estimates of CRFS described for each group along with pairwise comparisons.

Results

Baseline characteristics

A total of 346 patients were enrolled, of which 327 underwent transplantation. The median age was 51 years (range, 13−66 years) and the median time from diagnosis to HSCT was 5 months (range, 1.3−231 months). Treatment non-compliance rates were 14.4%, 8.2%, and 2.6% in the CD34⁺, PTCy, and Tac + MTX arms, respectively. Patient characteristics are shown in Table 1.

Table 1. Baseline characteristics*

Primary outcomes

CRFS was 50.6%, 48.1%, and 41.0% in the CD34⁺, PTCy, and Tac + MTX arms, respectively (Table 2).

• Compared with the Tac + MTX arm, the hazard ratios (HRs) for CRFS were 0.80 and 0.86 in the CD34+ and PTCy arms, respectively, and the HR was 0.93 comparing the CD34⁺ and PTCy arms (Table 3).
• The HR was 1.43 (p = 0.026) for CRFS in patients aged ≥50 years compared with younger patients.

Table 2. Primary and secondary outcomes*

Secondary outcomes

• The 2-year OS was 60.1%, 76.2%, and 76.1% in the CD34+, PTCy, Tac + MTX arms, respectively (Table 2).
  • Compared with the Tac + MTX arm, the HRs for OS were 1.74 and 1.02 in the CD34⁺ and PTCy arms, respectively, and the HR was 1.77 comparing the CD34⁺ and PTCy arms (Table 3).
• For overall mortality, patients aged ≥50 years compared with younger patients had a HR of 1.75 (p = 0.01), and high disease risk index compared with low or moderate was associated with a HR of 1.80 (p = 0.01).
• Cumulative incidences of moderate to severe cGvHD at 2 years was highest in the Tac + MTX arm compared with the CD34⁺ and PTCy arms (p < 0.001) (Table 2).
  • Patients in the CD34⁺ arm showed lower moderate to severe cGvHD compared with those in the PTCy arm (p = 0.02).
• Cumulative incidence of TRM at 2 years was highest among patients in the CD34⁺ arm compared with the PTCy and Tac + MTX arms (p = 0.020) (Table 2).
  • TRM was higher in patients aged ≥50 years compared with younger patients (HR, 3.29; p < 0.01).
• PTCy was associated with comparable cGvHD and survival outcomes to Tac + MTX, showing a trend toward lower disease relapse (p = 0.037) (Table 3).
• Cumulative incidences of Grade III infections at 2 years were 29.8%, 20.2%, and 14% for the CD34⁺, PTCy, and Tac + MTX arms, respectively (p = 0.014).
• Disease relapse was the most common cause of death; occurring in 45.2%, 48.1%, and 73.4% of patients in the CD34⁺, PTCy, and Tac + MTX arms, respectively.

Table 3. Pairwise treatment comparison*

Conclusion

This phase III study demonstrated that CD34⁺ selection or PTCy were not superior to Tac + MTX with BM in patients with HLA-matched transplantation. CD34⁺ selection showed significant reduction in cGvHD, however had higher rates of TRM. Although TRM, cGvHD, CRFS, and OS were similar for PTCy and Tac + MTX, PTCy was associated with more aGvHD. However, PTCy showed a trend towards improved relapse rate and relapse-free survival in comparison to Tac + MTX and CD34⁺ selection, respectively. Therefore, PTCy may be a transplant option in patients contraindicated to CNI or who require a CNI-free approach. Interestingly, this study demonstrated better TRM and OS for Tac + MTX compared with the experimental arms, but it was associated with the highest rate of cGvHD. Tac + MTX or PTCy and a BM graft offer improved survival rates >75% and should be considered the new standard approach for patients with hematologic malignancies. Further studies are warranted that focus on improving cGvHD and disease relapse using Tac + MTX, as well as investigating the effectiveness of PTCy + Tac + mycophenolate mofetil and anti-thymocyte globulin + Tac + MTX.