Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation

Abstract

The cumulative incidence of National Institutes of Health (NIH)-defined chronic graft-versus-host disease (GVHD) requiring systemic treatment is ∼35% at 1 year after transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized blood cells from HLA-matched related or unrelated donors. We hypothesized that high-dose cyclophosphamide given after G-CSF-mobilized blood cell transplantation would reduce the cumulative 1-year incidence of chronic GVHD to 15% or less. Forty-three patients with high-risk hematologic malignancies (median age, 43 years) were enrolled between December 2011 and September 2013. Twelve (28%) received grafts from related donors, and 31 (72%) received grafts from unrelated donors. Pretransplant conditioning consisted of fludarabine and targeted busulfan (n = 25) or total body irradiation (≥12 Gy; n = 18). Cyclophosphamide was given at 50 mg/kg per day on days 3 and 4 after transplantation, followed by cyclosporine starting on day 5. The cumulative 1-year incidence of NIH-defined chronic GVHD was 16% (95% confidence interval, 5-28%). The cumulative incidence estimates of grades 2-4 and 3-4 acute GVHD were 77% and 0%, respectively. At 2 years, the cumulative incidence estimates of nonrelapse mortality and recurrent malignancy were 14% and 17%, respectively, and overall survival was projected at 70%. Of the 42 patients followed for ≥1 year, 21 (50%) were relapse-free and alive without systemic immunosuppression at 1 year after transplantation. Thus, myeloablative pretransplant conditioning can be safely combined with high-dose cyclophosphamide after transplantation, and the risk of chronic GVHD associated with HLA-matched mobilized blood cell grafts can be substantially reduced. This trial was registered at www.clinicaltrials.gov as #NCT01427881.

© 2016 by The American Society of Hematology.

Figures

Figure 1

Preparative regimens. Participants in this study (n = 43) received 1 of 2 preparative regimens: (A) FLU/TBU (n = 25), which consisted of intravenous fludarabine 40 mg/m2 per day in combination with intravenous busulfan on days −5 until −2 (busulfan was targeted to steady-state concentrations of 800 to 900 ng/mL) or (B) fractionated TBI (n = 18) at a cumulative dose of 12 Gy or higher (12 Gy, n = 13; 13.2 Gy, n = 5) on days −5 until −2. In general, patients with myeloid malignancies received the FLU/TBU regimen, whereas those with lymphoid malignancies received TBI. G-CSF–mobilized peripheral blood mononuclear cells (≥5 × 106 CD34 cells/kg recipient weight) were infused on day 0. Cyclophosphamide (Cy) was given at 50 mg/kg per day intravenously on days 3 and 4 after transplant. An intravenous loading dose of CSP was given on day 5, followed by subsequent twice daily dosing adjusted to maintain whole blood trough concentrations at 120 to 360 ng/mL. In the absence of GVHD, CSP doses were tapered from day 56 through day 126.

Figure 2

Acute and chronic GVHD. (A) Cumulative incidence of acute GVHD. (B) Cumulative incidence of NIH-defined chronic GVHD (at 1 year: 16%; 95% CI, 5-28%). (C) Cumulative incidence of NIH-defined chronic GVHD according to donor type. (D) Cumulative incidence of NIH-defined chronic GVHD according to preparative regimen (HR, 0.55; 95% CI, 0.3-1.1; P = .09).

Figure 3

Overall survival, relapse, and NRM. Kaplan-Meier estimates of overall survival and cumulative incidence curves of NRM and relapse. At 2 years, the cumulative incidence estimates of NRM and recurrent malignancy were 14% and 17%, respectively, and survival was projected at 70%.

Figure 4

Kaplan-Meier survival estimates according to remission status at the time of transplant. Minimal residual disease (MRD)-neg complete remission (CR): 22 patients (51%) had disease in complete remission without minimal residual disease (AML, n = 12; ALL, n = 8; MDS, n = 2). MRD-pos CR: 14 patients (33%) were in morphologic remission but had evidence of minimal residual disease by virtue of flow cytometry, cytogenetic analysis, or fluorescence in situ hybridization (AML, n = 5; ALL, n = 5; MDS, n = 3; chronic myeloid leukemia [CML], n = 1). Other: 7 patients (16%) had >5% marrow blasts or detectable lymphoma (MDS, n = 4; CML, n = 2; non-Hodgkin lymphoma, n = 1). (A) Progression-free survival. (B) Overall survival. Comparing patients with MRD-positive CR to those with MRD-negative CR, progression-free survival and overall survival were statistically significantly different (P = .002 and P = .009, respectively).

Figure 5

Inductive effects of phenytoin (FLU/TBU; n = 22) compared with no phenytoin (TBI; n = 9) on cyclophosphamide metabolism. Boxplot shows median and interquartile ranges (25th and 75th percentile) of respective analyte AUC0-48h (μM⋅h). A statistically significant difference was observed between preparative regimens for the AUC of CY (P < .0001) and ketoCY (P = .03), but not the AUCs of CEPM and DCCY (P = .05 and 0.14; respectively).