Calcineurin inhibitors (CNIs) are the accepted backbone of acute GVHD prophylactic regimens following T-cell-replete allogeneic hematopoietic cell transplantation (HCT).1, 2 CNIs are commonly combined with other immunosuppressive agents such as MTX, mycophenolate mofetil (MMF), sirolimus (SIRO) and/or antithymocyte globulin (ATG) for improved prophylaxis. Although SIRO in combination with tacrolimus (TACRO) as GVHD prophylaxis has produced low rates of acute GVHD and nonrelapse mortality (NRM),3, 4, 5 this combination has also been associated with increased risk of endothelial injury syndromes such as sinusoidal obstruction syndrome6 and thrombotic microangiopathy,7 which often requires cessation of one or both drug(s) early after HCT. As MMF has no significant overlapping organ toxicities with TACRO or SIRO, we have used it as an alternative immunosuppressive drug for patients who must discontinue either TACRO or SIRO, or both as a result of early complications/toxicity. In this retrospective study we sought to evaluate the outcomes of patients who required early discontinuation of TACRO/SIRO, and were given MMF as salvage GVHD prophylaxis.
Between January 2009 and September 2011, a total of 411 consecutive patients with hematologic disorders underwent allogeneic HCT using TACRO/SIRO-based GVHD prophylaxis at our institution. TACRO was administered at 0.02 mg/kg/day intravenously by continuous infusion beginning on day −3 (target serum concentration, 5–10 ng/mL). It was converted to an equivalent oral dose before discharge. SIRO was administered as a 12 mg oral loading dose on day −3, followed by 4 mg/day thereafter (target serum concentration, 5–10 ng/mL). Levels were monitored twice weekly. With institutional review board approval, our chart review identified 56 patients (13.6%) who discontinued TACRO (n=23), SIRO (n=8) or both (n=25) within 30 days of transplant and then started MMF. Patients who received MMF after developing GVHD were excluded from the analysis as the study objective was to evaluate use of MMF as GVHD prevention. Following the start of MMF, steroids were administered within 30 days of transplant in 43 patients (76.8%) for the following indications: suspected or confirmed engraftment syndrome (n=16), respiratory issues (n=9), suspected or confirmed GVHD (n=9), suspected engraftment syndrome vs GVHD (n=4), prophylaxis for GVHD±adrenal stress dose (n=3) and confirmed or possible hemolytic uremic syndrome (n=2). Patients received either reduced-intensity conditioning with fludarabine/melphalan (n=49) or fully ablative conditioning with fractionated TBI (FTBI)/CY (n=7) followed by allogeneic HCT from related (n=13) or unrelated (n=43) donors (Table 1). All but one patient received peripheral blood hematopoietic stem cells. The planned GVHD prophylaxis was TACRO/SIRO only (n=45) for patients with ⩾8/8 HLA-matched donors, or TACRO/SIRO plus mini-MTX (n=8) or rabbit-ATG (n=3) for patients with <8/8 HLA-matched donors. Diagnoses included AML (n=11), myelodysplastic syndrome (n=15), non-Hodgkin's lymphoma (n=12), ALL (n=5), myeloproliferative disorder (n=6), CML (n=3), Hodgkin lymphoma (n=2), chronic myelomonocytic leukemia (n=1) and prolymphocytic leukemia (n=1). The Hematopoietic Cell Transplant-Comorbidity index (HCT-CI)8 was 0 in 33 (58.9%), 1–2 in 13 (23.2%) and ⩾3 in 10 patients (17.9%).
Patients started MMF at a median of 10 days post HCT (range: day −2 to day +30) due to renal dysfunction (n=25), thrombotic microangiopathy (n=13), confusion (n=7), sinusoidal obstruction syndrome (n=4), hypertriglyceridemia (n=2) or other TACRO/SIRO-related toxicities (n=5). Median serum creatinine level at MMF start, 1.31 mg/dl (range: 0.4–3.0 mg/dL), was significantly higher than at baseline, 0.84 mg/dL (range: 0.5–1.7 mg/dL) (P<0.0001). All but four patients (7%) engrafted with a median neutrophil engraftment time of 13 days (range: 8–24 days). Ultimately 27 patients (48%) developed grade II–IV acute GVHD (grade II: n=13; grade III–IV: n=14) with a median time to onset of 27 days (range: 6–86 days). Chronic GVHD developed in 32 patients (28 extensive and 4 limited) with median time to onset of 127 days (97–480); 14 patients died before the day-100 chronic GVHD evaluation and 10 patients did not develop chronic GVHD.
After a median follow-up of 15.2 months for surviving patients, the 1-year OS probability was 58.6% (95% confidence interval (CI): 44.0–70.6%), whereas 100-day and 1-year NRM rates were 19.6% (95% CI: 11.6–33.4%) and 29.5% (95% CI: 19.5–44.6%), respectively (Figure 1). The causes of death included relapse/disease progression in seven patients, acute GVHD in three, chronic GVHD in four, infection in three, graft failure in two, alveolar hemorrhage in two and others in five patients.
In this retrospective study, we observed a significant proportion of patients (13%) requiring discontinuation of TACRO/SIRO, and initiation of MMF early post HCT. This rate is higher than the 5% rate in our initial report of the phase II trial,5 owing to a larger percentage of high-risk patients in this study (77% unrelated donor HCTs, advanced disease status and so on). Using MMF-based salvage prophylaxis, the observed acute GVHD rate of 49% was not unexpected, considering that many patients had already experienced serious toxicities with first-line GVHD prophylaxis; only three deaths were attributable to acute GVHD. Furthermore, the NRM and OS rates were also in an acceptable range given the high-risk nature of these patients.
Johnston et al.9 conducted a phase II trial using SIRO and MMF for GVHD prevention in patients undergoing myeloablative HCT from sibling donors. The study showed a grade II–IV acute GVHD rate of 55%. All patients with GVHD responded to treatment and there were no GVHD-related deaths. Severe toxicities leading to SIRO discontinuation were seen only in patients receiving the BU-containing preparative regimen, consistent with prior reports. The authors suggested that SIRO/MMF-based CNI-free GVHD prophylaxis is similar in effectiveness to CNI-containing regimens and results in remarkably low nonrelapse mortality. Schleuning et al.10 evaluated the combination of MMF/SIRO/ATG in 14 patients in an observational cohort study, and showed that all evaluable patients (n=14) engrafted. Grades II–IV acute GVHD occurred in 21% and chronic GVHD in 30% of patients. They observed no thrombotic microangiopathy or sinusoidal obstruction syndrome in this cohort and NRM was 14%.
In summary, we observed acceptable rates of GVHD and OS/NRM using MMF in patients who discontinued TACRO/SIRO due to toxicities. Our data, together with other small studies, support the feasibility and possible value of CNI-free MMF-based GVHD prophylaxis for selected patients with high risk for CNI-related toxicities such as those with suboptimal renal function.
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This research was supported by the City of Hope Cancer Center staff with funding from NIH P30 Grant # CA33572.
The authors declare no conflict of interest.
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Ali, H., Palmer, J., Eroglu, Z. et al. Mycophenolate mofetil-based salvage as acute GVHD prophylaxis after early discontinuation of tacrolimus and/or sirolimus. Bone Marrow Transplant 50, 307–309 (2015). https://doi.org/10.1038/bmt.2014.245