Isavuconazole Prophylaxis during Early Phases of Allogeneic HSC Transplantation Is Not Associated to an Increase Need of Cyclosporin-a Dose Modification

Background: Isavuconazole is an effective treatment of invasive fungal infections (IFI). Since its broad spectrum of activity and favorable toxicity, it could also be used as a prophylaxis. Experience in use of isavuconazole as prophylaxis of IFI is, however, limited. In allogeneic transplant setting, its feasibility should also be assessed in regard of changes of Cyclosporine (CYA) metabolism.

Aim: To evaluate feasibility of the administration of Isavuconazole as short term prophylaxis during early phase of allogeneic transplantation and to study its influence on CYA trough blood levels and CYA dosing.

Methods: In a prospective study from July 2017 to April 2019, we treated 34 HSC transplantation using Isavuconazole (ISA) prophylaxis, ISA was administered at dosage of 200 mg /day i.v. (with a loading-dose of 200 mg x 3 /days for the first 48 hours) from day + 2 after HSCT infusion and until day + 30. The patients were selected using the criteria: any underlying diagnosis; age 18-70; any type of allogeneic donor; GVHD prophylaxis including CYA i.v.. Blood trough levels of CYA were measured bi-weekly by ELISA. Blood CYA level was maintained between 100 - 300 mcg/ml by dose adjustment. The need for CYA dose modification, IFI rate and patient outcome (TRM, OS) was studied and compared to an historical control group who received prophylaxis using Fluconazole during day +2 to day +30 (n 29).

Results:

Groups receiving Isavuconazole or Fluconazole were not significanly different in diagnosis, age, sex, disease status at transplant, donor type, stem cell-source, GVHD-prophylaxis and conditioning regimen. No patients in the Fluco-group had a previous invasive fungal infection (IFI), while 2 patients had a previously IFI in the Isa-group.

All patients reached engraftment, neutrophils engraftment was reached in a mean of 19 days and 18 days in the Isa and Fluco-group, respectively. No IFI occurred in the fluco-group, while 1 proven IFI (Blastoschyzomyces Capitatus blood-stream infection) occurred in the Isa-group. Mucositis occurred in 56 patients (88%). Mucositis grade III-IV grade of was registered in 62% and 61%, in the Isa- and Fluco-Group respectively. Isavuconazole was well tolerated, without significant toxicity, no patient needed dose-reduction or suspension.

Mean values of trough CyA blood-levels were compared at for 1^st, 2^nd, 3^rd and 4^th week and no difference was found between the two groups (Mann Whitney U test p value: 0.2, 0.5, 0.8, 0.9 respectively for 1^st, 2^nd, 3^rd and 4^th week), Fig 1. Mean number of CYA-dose adjustments was 1.3 /patient in Isa-group and 1.2/patient in Fluco-group. Difference was not significant (p = 0.6, Mann-Whitney U-test).

Overall survival (OS) at 1 year was 64 % in Fluco-group (95% CI: 44-79%) and 66% in Isa-group (95% CI: 44-81%) (log-rank, p value: 0.9). Non-relapse mortality (NRM) at 1 year was 16.3% (95% CI: 5.7-31%) in Isa-group and 14.2% (95% CI:4.3-29%) in Fluco-group (Gray test, p: 0.61).

Conclusions:

In this prospective study, short term prophylaxis using Isavuconazole, after allogeneic HSC transplant, was found to be feasible. No significant difference with standard fluconazole prophylaxis was found in trough CYA blood levels and in the need of cyclosporin dose modification. Further studies are needed extending the lenght of Isavuconazole prophylaxis.

Figure 1

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Figure 1

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