The Effects of Mycophenolate Mofetil and Cyclosporine with Concomitant Posaconazole Tablets in the Early Stage of Allogeneic Hematopoietic Stem Cell Transplantation

Background：

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) mainly applied the “Beijing regimen”(cyclosporine + methotrexate + mycophenolate mofetil（MMF）). This approach significantly reduces the risk of graft-versus-host disease (GVHD), increases the risk of infection. Posaconazole can significantly reduce the incidence of invasive fungal disease (IFD) during the immunosuppressive phase. Cyclosporine and posaconazole have significant drug interactions, with MMF also have drug interactions. However, there is limited research about drug interactions of simultaneous three-drug combination.

Objective：

Explore the effects of MMF and cyclosporine with concomitant posaconazole in allo-HSCT patients within 30 days and the breakthrough incidence of IFD within 100 days post-transplantation.

Method:

A single-arm, open-label, prospective trial was conducted to evaluate posaconazole tablet (300 mg q12h oral d1,300 mg/d) as secondary antifungal prophylaxis in allo-HSCT patients (18-65 years old) with previous proven or probable IFD (ChiCTR2200059472). Posaconazole and cyclosporine were started when conditioning began, while MMF was used one day before infusion of stem cell for one month with fixed dose of 2 g/d. The plasma concentration of posaconazole and mycophenolic acid (MPA) which is the active ingredient of MMF, were monitored weekly, cyclosporine was monitored twice one week until 30 days post-transplantation.

Results:

Thirty patients from July 2022 to March 2023 were enrolled in the trial, included 16 males and 14 females, acute myelogenous leukemia 22, acute lymphoblastic leukemia 2, myelodysplastic syndrome 2, aplastic anemia 4. All patients underwent haploidentical HSCT. All patients had history of IFD(5 proven IFD, 13 probable IFD and 12 possible IFD).

At week1, 2, 3 and 4 after conditioning, The mean plasma concentrations of posaconazole were 0.47±0.29ug/ml, 0.66±0.32ug/ml,0.72±0.40ug/ml and 0.91±0.32ug/ml（Figure 1）. The mean plasma concentrations of cyclosporine were 138.20±35.33ng/ml, 190.61±48.07ng/ml,245.46±37.31ng/ml and 253.56±45.19ng/ml（Figure 2）.The mean plasma concentrations of MPA at week 2, 3 and 4 were 0.35±0.15mg/L, 0.89±0.36mg/L and 1.18±0.58mg/L (Figure 3). After week 1, concentration of cyclosporine of 13 cases was below 150ng/ml and the dosage was increased by 25% of the original dose, at week 4, concentration of cyclosporine of 9 cases was above 250ng/ml and the dosage was decreased by 25%.

After posaconazole reached steady state concentrations at week 2, while cyclosporine reached target concentrations after the dose increase, MPA did not reach target concentrations at week 2. The concentrations of MPA significant increase without changing the MMF dose and reached target concentrations at week 3 simultaneous three-drug combination. Cyclosporine concentrations increased significantly at week 4 with stable concentrations of MPA and posaconazole, and 30% of patients required dose reduction of cyclosporine.

Only one patient was diagnosed as aspergillus fumigatus pneumonia through NGS of pulmonary alveolar lavage fluid. The breakthrough incidence of IFD was 3.33%.

Conclusion:

Different times of administration lead to different times of interaction among the three drugs. The combination of cyclosporine and MMF leads to decrease in MPA concentrations, but the concentration of MPA can rapidly increase when combined with posaconazole. When target concentration of MPA is not reached in the first week, it is recommended to suspend dose modification and TDM in the second week. However, the accumulation of cyclosporine was significant in the fourth week, and it was recommended that cyclosporine should be monitored and adjusted within three weeks after the three drugs were combined.

The cumulative breakthrough incidence of 3.33% is lower than reported in literaturesuggesting that posaconazole appears to be effective for secondary prophylaxis of IFD after allo-HSCT.