Grade II Acute Graft-versus-Host Disease and Higher Nucleated Cell Graft Dose Improve Progression-Free Survival after HLA-Haploidentical Transplant with Post-Transplant Cyclophosphamide

Abstract

Compared with standard graft-versus-host disease (GVHD) prophylaxis platforms, post-transplantation cyclophosphamide (PTCy) after T cell-replete HLA-haploidentical (haplo) bone marrow transplantation (BMT) reduces the risk of grades III to IV acute (a) and chronic (c) GVHD, but maintains similar rates of grade II aGVHD. Given that mild GVHD has been associated with reduced treatment failure in HLA-matched BMT, we evaluated the risk factors for and effects of GVHD on survival in 340 adults with hematologic malignancies who engrafted after nonmyeloablative haplo-BMT with PTCy, mycophenolate mofetil, and tacrolimus. The cumulative incidence at 100 days of grade II and grades III to IV aGVHD were 30% (95% confidence interval [CI], 25% to 35%) and 2% (95% CI, 1% to 4%), respectively. The 1-year cumulative incidence of cGVHD was 10% (95% CI, 7% to 13%). In landmark analyses at 100 days, the 4-year probabilities of overall survival (OS) and progression-free survival (PFS) were, 48% (95% CI, 41% to 56%) and 39% (95% CI, 32% to 47%) for patients without grades II to IV aGVHD, compared with 63% (95% CI, 53% to 73%) and 59% (95% CI, 50% to 71%) for patients with grade II aGVHD (P = .05 and P = .009). In multivariable modeling, when compared with patients who never experienced GVHD, the hazard ratio (HR) for OS and PFS in patients with grade II aGVHD was .78 (95% CI, .54 to 1.13; P = .19) and .69 (95% CI, .48 to .98; P = .04). Higher nucleated cell graft dose was also associated with improved OS (HR, .88; 95% CI, .78 to 1.00; P = .05) and PFS (HR, .89; 95% CI, .79 to 1.0; P = .05) and decreased risk of grades III to IV aGVHD (subdistribution HR, .66; 95% CI, .46 to .96; P = .03). PTCy reduces grades III to IV aGVHD and cGVHD, but retains similar incidence of grade II aGVHD, the development of which improves PFS. Higher nucleated cell graft dose goals may also improve survival after nonmyeloablative haplo-BMT with PTCy.

Keywords: Bone marrow transplantation; Cyclophosphamide; Graft dose; Graft-versus-host disease; HLA-haploidentical.

Figure 1.

(A) In patients who were alive at day 100, the probabilities of OS (P = .05) and PFS (P = .009) were significantly better in patients who had developed grade II aGVHD (OS, dark blue line; PFS, hash-marked light blue line) when compared with patients who had not developed grades II to IV aGVHD (OS, black line; PFS, hash-marked gray line). (B) In patients who were alive and without relapse at day 100, CuI of relapse was significantly less (P < .001) in patients who had developed grade II aGVHD (dark blue line) when compared with patients who had not developed grades II to IV aGVHD (black line). CuI of NRM was not significantly different in patients who had developed grade II aGVHD (hash-marked light blue line) when compared with patients who had not developed grades II to IV aGVHD (hash-marked gray line). no GVHD24 indicates patients alive and without grades II to IV aGVHD by 100 days; aGVHD2, patients alive and having already developed grade II aGVHD by 100 days; no, number at risk; no a24, patients alive and without aGVHD; a2 patients alive and having already developed grade II aGVHD

Figure 2.

(A) In patients who were alive at 1 year, the probability of OS and PFS was not significantly different in patients who had developed cGVHD (OS, dark yellow line; PFS, hash-marked light yellow line) when compared with patients who had not developed GVHD (OS, black line; PFS, hash-marked gray line). (B) In patients who were alive and without relapse at 1 year, CuI of relapse was significantly lower in patients who developed cGVHD (dark yellow line) when compared with patients who had not developed GVHD (black line). CuI of NRM was significantly different in patients who developed cGVHD (hash-marked light yellow line) when compared with patients who had not developed GVHD (hash-marked gray line). no GVHD indicates patients alive and without aGVHD or cGVHD by 1 year; cGVHD, patients alive and having developed cGVHD by 1 year.

Figure 3.

PFS was examined in subgroups by forest plots. In the group as a whole (shown as Summary), patients benefited from grade II aGVHD. All individual subgroups, except for CMV-positive recipients, benefited from grade II aGVHD. AML indicates acute myelogenous leukemia; MDS, includes myelodysplastic syndrome and myeloproliferative neoplasms (chronic myelogenous leukemia and chronic myelomonocytic leukemia); ALL, acute lymphoblastic leukemia; Agg Lymph, aggressive non-Hodgkin lymphoma including mantle cell; Indo Lymph, indolent non-Hodgkin lymphoma including chronic lymphocytic leukemia; Hod Lymph, Hodgkin lymphoma; Mult Myeloma, multiple myeloma; NR, not run; CR, complete response; MRD, minimal residual disease; DAge, donor age; Not Fem2Male, includes male into male, male into female, or female into female allografts; Fem2Male, includes female into male allografts only; NC, total nucleated cells per kilogram of ideal body weight.