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.

Development of Grade II Acute Graft-versus-Host Disease Is Associated with Improved Survival after Myeloablative HLA-Matched Bone Marrow Transplantation using Single-Agent Post-Transplant Cyclophosphamide

“…We have previously shown that high-dose PTCy is an effective single-agent prophylactic strategy after HLA-matched BMT [10–13] and seems to reduce severe aGVHD and cGVHD without concomitant decreases in the incidence of grade II aGVHD. Similar to recent studies in haplo BMT with PTCy [9] and umbilical cord transplantation [30] we demonstrate that grade II aGVHD is associated with significantly improved OS and PFS in HLA-matched BMT with PTCy. We believe that this is due to retention of the graft-versus-tumor effect with grade II aGVHD, but absence of the long-term morbidity and late mortality associated with moderate and severe cGVHD.…”

“…We believe that this is due to retention of the graft-versus-tumor effect with grade II aGVHD, but absence of the long-term morbidity and late mortality associated with moderate and severe cGVHD. The replication of our findings in haplo BMT [9] in this HLA-matched cohort treated with PTCy suggests that PTCy successfully modulates alloreactivity; thus, most mild aGVHD cases do not progress to higher grades of aGVHD or to cGVHD nor increase NRM, yet anti-tumor efficacy is maintained.…”

“…We have previously shown that PTCy minimizes the global immunosuppressive burden experienced by patients undergoing HLA-matched BMT [15], and this work emphasizes the importance of exploring the further minimization of pharmacologic agents post-transplant in other platforms such as reported recently by our group in haplo BMT with PTCy [39]. Although this and other recent studies [9,15,39,40] suggest that potent anti-tumor immune responses are maintained with PTCy, fully deciphering these interactions requires further mechanistic studies.…”

“…We have now demonstrated, clinically, what was demonstrated years ago in murine experiments: that control of severe GVHD with preservation of anti-leukemic effects can be seen with PTCy given at specific dosing and timing after allografting. Furthermore, we have demonstrated similar effects with differing PTCy-based BMT platforms: HLA-matched BMT and haplo BMT [9]. …”

Shortened-Duration Tacrolimus after Nonmyeloablative, HLA-Haploidentical Bone Marrow Transplantation

“…An interim assessment of the day +60 tacrolimus cohort triggered an accrual pause due to a potential increase in grade II-IV GVHD. There was no apparent increased incidence of grade III-IV GVHD or NRM, and emerging data suggested that grade II limited GVHD after haplo BMT is associated with improved progression-free survival (PFS) [18]. The GVHD stopping rule was modified and study of day +60 tacrolimus cessation continued with Institutional Review Board approval.…”