Graft-Versus-Host Disease (Gvhd) Prophylaxis with Tacrolimus and Mycophenolate Mofetil (MMF) in 131 Matched Sibling Nonmyeloablative (NMA) Transplant Recipients: Long-Term Follow-up Confirms Extremely Low Incidence of Acute (a) Gvhd, High Incidence of Extensive Chronic (c) Gvhd and Favorable Disease Outcome.

Incidences of grade II–IV aGvhd in the range of 30–50% have been reported in sibling NMA transplant recipients despite prophylaxis with cyclosporine and methotrexate. To date, the ideal Gvhd prophylaxis regimen still remains undefined. Because tacrolimus is more potent than cyclosporine and MMF does not lead to mucositis, we hypothesized that early use of a combination of these two oral agents could offer an effective strategy to prevent Gvhd. We therefore designed an outpatient prospective phase II clinical trial with a NMA conditioning regimen consisting of daily fludarabine 30 mg/m² and cyclophosphamide 300 mg/m² for 5 days, followed by infusion of at least 4 × 10⁶ CD34+ cells/kg. All donors were 6/6 matched siblings. Tacrolimus 3 mg bid orally was started on day (D)-8, adjusted to achieve levels of 10–15 nmol/L until D+50, then tapered off by D+100 or +180 according to estimated risk of relapse. MMF 1000 mg bid was given between D+1 to D+50 without taper. Enrollment criteria included age >55 years, an estimated increased risk of toxicity with an ablative transplant or participation in a multiple myeloma (MM) sequential therapy. Between 07/2000 and 07/2007, 131 patients (M/F: 75/56) with a median age of 54 years (range: 20–66) have received an allogeneic transplant according to our protocol. Indication for transplant included age (26%), fear of toxicity (28%) or participation in the sequential therapy (48%). Overall, 101 (77%) patients had previously received an autologous transplant. Diagnoses included MM (N=62), non Hodgkin’s lymphoma (NHL; N=46) including low grade (N=33), diffuse large cell (N=5), mantle (N=7) and Sezary (N=1), acute leukemia (N=10), and others (N=13). After infusion of a median of 6.8 × 10⁶ CD34+ cells/kg (range 0.30 to 22.3), engraftment occurred in 95% of patients by D+180. Overall, 15 patients developed grade I–IV conventional aGvhd by D+120, with a Kaplan-Meier (KM) probability of 11.6% (95%CI: 7.1–18.5), a median of 64 (range: 31–120) days after transplant. At presentation, aGvhd grade was I in 5, II in 7, and III in 3 patients, respectively. No grade IV was observed. Organs involved included skin (13/15) or gastro-intestinal (GI; 4/15), but not liver. Additionally, 15 patients (12%; 95%CI: 7.4–19.2) developed an overlap syndrome consisting of clinical and histological features of both acute and cGvhd simultaneously, at a median of 140 (range 92–177) days post transplant. Altogether, the incidence of conventional II–IV aGvhd and overlap syndrome was 19.7% (95%CI: 13.7–27.7). In contrast, extensive cGvhd occurred in 84 patients surviving beyond D+80 (median D+148, range 83–1042), with a cumulative KM incidence at 7 years of 83.3% (95%CI: 74.3–90.6). Involved organs at diagnosis of extensive cGvhd included mouth (100%), skin (89%), liver (65%), eyes (51%), GI (20%), joints (6%) and lungs (6%), similar to other reported series. Nine of 76 (12%) patients at risk are still taking immunosuppressors after 5 years. To date, 37 patients have died; causes of death include relapse of initial malignancy (N=24), cGvhd (N=3), viral or fungal infection (N=3), or other (N=7). With a cohort median follow-up of 33 (range 2.7–86) months, KM probability of non-relapse mortality (NRM) is 15.5% (95% CI: 9.0–26.1) at 7 years. Overall survival (OS) at 1, 3 and 7 years are 88.5% (95%CI: 81.7–92.9), 71.0% (95%CI: 61.1–78.7) and 62.7% (CI: 51.4–72.1), respectively. Following NMA transplant, disease-free survival (DFS) at 3 years is highest in recipients with low-grade NHL (81.4%; 95%CI: 60.5–91.9) and lowest in intermediate grade NHL (40.0%; 95%CI: 6.6–73.4) or leukemia (35.7%; 95%CI: 13.0–59.4). We conclude that early use of tacrolimus and MMF is an effective strategy to prevent aGvhd and leads to very low NRM. Despite a high incidence of extensive cGvhd, OS, DFS and probability of discontinuing immunosuppression are excellent. Future strategies will need to focus on decreasing the incidence of extensive cGvhd without increasing the risk of relapse.