Daily Monitoring of Cyclosporine (Csa) Allows Better Control of Graft vs. Leukaemia Effect (GvL): Single Centre Experience.

The most important consideration in modern SCT practices is the fine balance that is required to achieve adequate immunosuppression and stable engraftment thus allowing the platform to mount an effective GVL response. Though CsA facilitates this objective, it is associated with several adverse clinical manifestations due to its narrow therapeutic index (TI) and wide variability in the absorption kinetics. Weekly monitoring of trough CsA levels are used to adjust the dose. The aim of this study is to determine whether daily monitoring of CsA levels enables better achievement of these goals and yet reduce the serious toxicities.

Patients & methods: Twenty three patients (M=15, F=8, median age 46yrs range 19–63) received an allogeneic transplant (sibling-15, MUD-7 mismatched unrelated-1) since March 2004 when we started to monitor daily CsA levels (Biostat TDX analyser using fluorescent immunoassay) from the day of first administration until the time of discharge. The transplants included full intensity (FI=11), reduced intensity (RI=11) or customised (1) for various haematolymphoid malignancies. Patients received uniform GVHD prophylaxis with IV CsA (RI+FI) and methotrexate (FI) as per standard loading doses. The CsA target level was adjusted to 200–220 ng/ml from Day-1 onwards and was later modified according to the treatment strategy. Oral CsA administration was started when patients were able to switch over. Results Nine of 23 (40%) patients developed acute GVH (n=7 grade1–2, n=2 grade 3–4) at a median of 23.5 days (10–28). Two of 9 patients required addition of steroids by Day+30. The median CsA level at the first occurrence of GVH was 247ng/ml (113–333) and the median CsA level during hospitalisation was 207 ng/ml (136–291). Only one patient who received T cell addback required increased dose of IV CsA to manage Grade 4 GVH. Twenty two/22 patients engrafted with a median day to neutrophil recovery being 13 days (8–35). One patient lost his graft due to a low initial cell dose and the inability of the MUD donor to donate any further cells. There was no significant difference in the baseline and Day30 creatinine levels (median highest creatinine 108μmol/l range 58–267) or bilirubin levels (median highest bilirubin 27μmol/l, range15–251). Five/22 patients developed CMV reactivation/infection and 1 developed RSV infection. No patients developed seizures and in one patient pre-existent neuropathy was exacerbated which was directly attributable to CsA. Twenty one/22 patients (95.5%) switched to oral CsA by Day+25. In 8/22 (36.36%) patients, the target CsA levels was around 100–150 ng/ml at the time of discharge. The median duration of hospital stay was 35days (24–130).

Conclusions: These observations suggests that daily monitoring of CsA is safe and successful. This allowed successful engraftment and a more liberal management of Grade 1–2 GVH thus allowing us to maximise the GVL effect. Despite concomitant use of other toxic drugs, side effects were minimal and reversible. Close observation of early clinical manifestations enabled us to modify the immunosuppressive strategy at later time periods. This approach also allowed us to better manage patients suffering from CMV and EBV/PTLD (patient number 10 on day+88) by reducing the dose during active infections.