Results from the phase II BMT CTN 1203 study: Comparison of 3 reduced intensity conditioning regimens to prevent GvHD with hematopoietic cell transplantation

Methotrexate and cyclosporine have been the standard prophylactic treatment in patients undergoing human leukocyte antigen (HLA)-matched bone marrow transplantation to prevent graft-versus-host disease (GvHD). Cyclophosphamide, maraviroc and bortezomib-based combinations have all shown efficacy in preventing GvHD but no study has yet compared these to one another, or to the standard treatment.

Using the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), promising GvHD prophylactic interventions were selected to be studied prospectively. The BMT CTN 1203 multicenter, open-label, phase II study (NCT02208037) investigated regimens containing maraviroc, bortezomib or post-transplantation cyclophosphamide as prophylactic treatments for GvHD compared to tacrolimus and methotrexate controls. The aim of the study was to identify the intervention that should be taken into a phase III trial using a novel composite primary endpoint.

This study by Javier Bolaños-Meade, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, Ran Reshef, Columbia University Medical Center, New York, NY, and colleagues was published in Lancet Haematology.

Patient characteristics and study design

• Adult patients aged 18–75 who were candidates for reduced-intensity conditioning hematopoietic cell transplant (HCT) were recruited, following the decision to undertake transplant and once a suitable HLA-matched donor had been identified
• Eligible diseases included; acute leukemia, chronic myelogenous leukemia and myelodysplasia, chronic lymphocytic leukemia or small lymphocytic lymphoma, and follicular, marginal zone, diffuse large-B cell, Hodgkin or mantle cell lymphoma
• Randomized 1:1:1 to (n = 273):
  • Tacrolimus, mycophenolate mofetil and post-transplant cyclophosphamide (n = 92) (TAC, MMF, and PTCY)
  • Tacrolimus, methotrexate and, bortezomib (n = 89) (TAC, MTX and BOR)
  • Tacrolimus, methotrexate and, maraviroc (n = 92) (TAC, MTX and MVC)
  • See end of the article for the dosing regimens*
  • Randomization used permuted blocks of random sizes and was stratified by donor type and disease risk
• Comparison of each study group versus a non-randomized control group (n = 224)
  • Control group: prospective cohort of patients treated with tacrolimus and methotrexate
  • All fit the eligibility criteria of the study
• Dose reductions were permitted for tacrolimus, methotrexate and maraviroc and were also permitted for bortezomib, with discontinuation allowed in the event of grade 4 neuropathy. No dose adjustments were made for post-transplant cyclophosphamide
• Primary endpoint (composite): GvHD-free, relapse-free survival (GRFS) defined as the time from HCT to onset of grade 3-4 acute GvHD (aGvHD), chronic GvHD (cGvHD) needing systemic immunosuppressants, disease relapse or progression, death (any cause), loss to follow-up or the end of one year
• Secondary endpoints: cumulative incidences of grade 2–4 and grade 3–4 aGvHD and cGvHD, one-year immunosuppression-free survival, neutrophil and platelet recovery, donor cell engraftment, disease relapse or progression, transplant-related mortality (TRM), toxicities, infections, disease-free survival (DFS), GvHD-free survival, overall survival (OS) and causes of death
• For results, each regimen was compared to the control group in the endpoints listed above, aside from donor cell engraftment, toxicities, infections, and causes of death
• Median age: 64 years (interquartile range [IQR] 59–68)

Efficacy:

• GFRS: Kaplan-Meier estimates for GRFS at 1-year (90% CI):
  • Control: 34% (28–40)
  • TAC, MMF and PTCY: 43% (34–54)
  • TAC, MTX and BOR: 35% (27–47)
  • TAC, MTX and MVC: 28% (20–38)
• GFRS: Hazard ratios for GRFS compared to controls (90% CI):
  • TAC, MMF and PTCY: 0.72 (0.54–0.94, P = 0.044)
  • TAC, MTX and BOR: 0.98 (0.76–1.27, P = 0.92)
  • TAC, MTX and MVC: 1.10 (0.86–1.41, P = 0.49)
• Neutrophil recovery: no difference between regimens
• Graft failure by day 100 (P = 0.65):
  • TAC, MMF and PTCY: 4% (n = 3)
  • TAC, MTX and BOR: 6% (n = 5)
  • TAC, MTX and MVC: 4% (n = 3)
• Cumulative incidence of aGvHD at day 180 (grades 2–4 vs grades 3–4) (90% CI):
  • Control: 30% (25–36) vs 13% (9–16)
  • TAC, MMF and PTCY: 27% (20–35) vs 2% (0–5)
  • TAC, MTX and BOR: 26% (19–34) vs 8% (4–13)
  • TAC, MTX and MVC: 32% (24–40) vs 9% (4–14)
• Cumulative incidence of cGvHD at 1-year (cGvHD vs cGvHD requiring immunosuppression) (90% CI):
  • Control: 38% (33–43) vs 37% (31–42)
  • TAC, MMF and PTCY: 28% (20–36) vs 22% (15–30)
  • TAC, MTX and BOR: 39% (30–48) vs 29% (22–38)
  • TAC, MTX and MVC: 43% (35–52) vs 33% (25–41)
• Disease relapse/progression and TRM (1-year cumulative incidence), and 1-year estimates of DFS and OS were comparable across regimens
• At 1-year, patients alive and relapse free:
  • Control: 56% (75/135)
  • TAC, MMF and PTCY: 71% (40/56, P = 0.041)
  • TAC, MTX and BOR: 67% (35/52, P = 0.14)
  • TAC, MTX and MVC: 57% (28/49, P = 0.85)

Safety:

• All data
• Total grade 3 and 4 toxicities: n = 238
  • Given as grade 3 versus grade 4
    • TAC, MMF and PTCY: 13% (n = 12) vs 73% (n = 67)
    • TAC, MTX and BOR: 11% (n = 10) vs 76% (n = 68)
    • TAC, MTX and MVC: 20% (n = 18) vs 68% (n = 63)
• Most common toxicities were hematological (84%, 228/273) and cardiac (48%, 130/273)
  • Given as hematological versus cardiac
    • TAC, MMF and PTCY: 84% (n = 77) and 47% (n = 43)
    • TAC, MTX and BOR: 82% (n = 73) and 49% (n = 44)
    • TAC, MTX and MVC: 85% (n = 78) and 47% (n = 43)

Conclusion

When compared to the control group, the tacrolimus, mycophenolate mofetil and post-transplantation cyclophosphamide arm was the only intervention to show an improved GFRS due to low rates of severe aGvHD and cGvHD requiring immunosuppression. These results have supported the launch of a phase III study (BMT CTN 1703) prospectively comparing high-dose post-transplantation cyclophosphamide with methotrexate and a calcineurin inhibitor.

*Regimen specific dosing:

TAC, MMF, and PTCY

• Post-transplantation cyclophosphamide: 50 mg/kg on days 3 and 4
• Tacrolimus and mycophenolate mofetil: 15 mg/kg starting on day 5.
  • Three times per day, not exceeding 1 g three times daily
  • On day 35, mycophenolate mofetil was stopped

TAC, MTX, and BOR

• Bortezomib: 1.3 mg/m² intravenously on days 1, 4 and 7
• Tacrolimus
  • Intravenous: 0.05 mg/kg twice daily starting on day 3, oral equivalent was permitted
  • Target level: 5–15 ng/mL
  • Recommended to be continued until day 90
  • Stopped (tapered) by day 180
• Methotrexate (post-HCT)
  • Intravenous bolus of 15 mg/m² on day 1
  • Intravenous bolus of 10 mg/m² on days 3, 6 and 11

TAC, MTX, and MVC:

• Maraviroc: 300 mg orally, twice daily from day 3–30
• Tacrolimus
  • Intravenous: 0.05 mg/kg twice daily starting on day 3, oral equivalent was permitted
  • Target level: 5–15 ng/mL
  • Recommended to be continued until day 90
  • Stopped (tapered) by day 180
• Methotrexate
  • Intravenous bolus of 15 mg/m² on day 1
  • Intravenous bolus of 10 mg/m² on days 3, 6 and 11