Effect of Early Post-Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

Abstract

Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as a GVHD prophylaxis. However, there is variability in the serum concentrations of TAC, and little is known on the impact of early TAC levels on aGVHD. We retrospectively analyzed 673 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002 and 2016. Week 1 TAC was associated with a lower risk of aGVHD II–IV at TAC level ≥10.15 ng/mL (p = 0.03) compared to the lowest quartile. The cumulative incidence of relapse at 1, 3 and 5 years was 33%, 38% and 41%, respectively. TAC levels at week 2, ≥11.55 ng/mL, were associated with an increased risk of relapse (p = 0.01) compared to the lowest quartile. Subset analysis with acute myeloid leukemia and myelodysplastic syndrome patients showed significantly reduced aGVHD with TAC level ≥10.15 ng/mL at week 1 and a higher risk of relapse associated with week 2 TAC level ≥11.55 ng/mL (p = 0.02). Hence, achieving ≥10 ng/mL during the first week of HCT may mitigate the risk of aGVHD. However, levels (>11 ng/mL) beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse.

Tacrolimus initial steady state level in post-transplant cyclophosphamide-based GvHD prophylaxis regimens

“…One reasonable explanation is that early lower levels of suppression (TISS <10 ug/mL) permitted GvL that likely contributed to lower RR. TISS was not correlated with aGvHD or cGvHD in our analysis, as noted in TAC/methotrexate-based regimen( 22 , 29 ), which is possibly due to the upfront effect of PTCy on T cells before TAC is introduced. In our analysis, PBSCs as the graft source was the only predictor of risk of aGvHD grade II-IV, which is comparable to published data( 5 , 7 ).…”

“…When combined with methotrexate, higher early (first week) TAC level was associated with lower risk of aGvHD grade II-IV in RIC setting( 22 , 29 ), but less GvL with higher RR( 29 ). We observed a trend of better DFS with lower RR in patients with TISS <10 ng/mL vs. ≥10 ng/mL without affecting GvHD and NRM.…”

“…Despite the increased use of PTCy combined with TAC, there are currently no standard dosing guidelines or therapeutic target serum levels for TAC. It is assumed that immunosuppressive levels pre-engraftment could impact T cell repertoire and recovery, which may dictate the incidence and severity of GvHD( 22 – 29 ), the graft-versus-leukemia (GvL) effect and transplant outcomes. TISS represents an early adjustable timepoint where intervention could lead to better outcomes.…”

Letermovir Prophylaxis and Cytomegalovirus Reactivation in Adult Hematopoietic Cell Transplant Recipients with and without Acute Graft Versus Host Disease

“…The rates of aGVHD grade ≥ 2 reported in this study in both the letermovir group and control group (55.4% and 54.5%, respectively) are relatively high compared to averages previously published in the literature. The majority of our patient population (78%) received matched unrelated, mismatched unrelated, or haploidentical transplants, which are known to have a higher risk of GVHD compared to a matched related donor transplant [ 20 , 21 ]. Peripheral blood was the most common stem cell source in our patient population (77%), which also has an increased risk of GVHD compared to bone marrow or cord blood stem cell source [ 22 ].…”

Retention of Donor T Cells in Lymphohematopoietic Tissue and Augmentation of Tissue PD-L1 Protection for Prevention of GVHD While Preserving GVL Activity

“…GVHD target tissues include the skin, lung, liver and intestine ( 12 ), but leukemia/lymphoma cells reside mainly in lympho-hematopoietic tissues, including the bone marrow, spleen and lymph nodes ( 13 ). Current methods that suppress general alloreactive T cell activation and expansion such as immunosuppressants (i.e., tacrolimus and sirolimus) simultaneously reduce GVHD and GVL activity ( 14 , 15 ). Blocking alloreactive T cell infiltration in GVHD target tissues while allowing full activation and expansion of alloreactive T cells that kill malignant cells in the lympho-hematopoietic compartment offers a better approach toward prevention of GVHD.…”