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  • The patient was consented to treatment on clinical trial

    2019-05-23

    The patient was consented to treatment on clinical trial NCT02527447 and received treatment with salvage chemotherapy of mitoxantrone 12mg/m2/day IV on days 1–3, etoposide 200mg/m2/day continuous IV infusion (CIV) on days 8–10, and cytarabine 500mg/m2/day CIV on days 1–3 and 8–10 (EMA). Infectious prophylaxis with caspofungin was given during chemotherapy and oral posaconazole was started after chemotherapy as per institutional standard. During the third week after chemotherapy, new painful nodules appeared on his trunk, neck, upper arm and the plantar aspect of his foot. In addition, there was interval development of bilateral focal patchy nodular pulmonary infiltrates with ground glass and reticular appearance on chest CT imaging (Fig. 1C/D), followed by development of paranasal sinusitis. The patient underwent bronchoscopy with broncho-alveolar lavage, ion channels biopsy of a palpable nodule, and sinus biopsy. Fusarium solani was isolated from all three of these sites (Fig. 1F/G). Fungal susceptibilities showed amphotericin minimum inhibitory concentration (MIC): 2mcg/mL and terbinafine MIC: 2mcg/mL and resistance to micafungin, posaconazole and voriconazole. The patient was initially treated with amphotericin, however, subsequent CT chest one week later showed progression of pulmonary infiltrates, and terbinafine and voriconazole were added despite fungal susceptibilities. Bone marrow examination on day 35 showed a hypocellular (5%) marrow with trilineage hypoplasia and no definitive evidence of AML. Peripheral blood neutrophils were absent. A course of filgrastim daily injections was administered for ten days, at which time his absolute neutrophil count (ANC) recovered to greater than 2.0 × 109/L. The total duration of severe neutropenia with ANC less than 0.1 × 109/L was 40 days. At the time of ANC recovery, the result of his Fungitell serum assay (Beacon diagnostics) was positive (167pg/mL, positive = > 80pg/mL), however, the appearance of his skin nodules improved, and pulmonary and sinus radiographic abnormalities stabilized during this time. Complete remission with no evidence of minimal residual disease was confirmed on bone marrow examination on day 73. At day 100 following salvage chemotherapy, the CT showed resolution of the nodules (Fig. 1E) and Fungitell result normalized (< 60pg/mL, Fig. 2A). He received consolidation chemotherapy with clofarabine 20mg/m2 IV on days 1–5, followed by haplo-identical SCT 10 days later. A two-step approach [3] was used as a myeloablative conditioning regimen including fludarabine 120mg/m2, total body irradiation (12Gy), and a donor lymphocyte infusion (2 × 108/kg CD3+T cells) which was followed by cyclophosphamide 120mg/kg prior to CD34+ selected peripheral blood stem cell infusion. GVHD prophylaxis was with sirolimus (trough goal 5–12ng/mL) along with ultra-low dose interleukin-2 (ULD-IL2) 100,000 international units/m2(clinical trial NCT02226861). Micafungin was used as anti-fungal prophylaxis until day 33 following post-transplant. No other anti-fungal prophylaxis therapy was used. The patient became neutropenic (ANC < 0.5 × 109/L) from clofarabine consolidation 10 days prior to stem cell graft infusion, and the time to engraftment (ANC > 0.5 × 109/L) was 12 days following transplant, for a total of 22 days of peri-transplant neutropenia. Due to the anticipated neutropenia, granulocyte infusions from G-CSF stimulated donors were scheduled for 5 doses during his transplant course (Fig. 2B) with average dose more than 0.6 × 109/kg. Granulocyte donors were selected based on negative CMV serology and to avoid any HLA class I and II antigen mismatch with the patient or haplo-identical SCT donor. Granulocyte infusions were well tolerated without complications. G-CSF was not used in the peri-transplant period. The patient is now 14 months’ post haplo-identical SCT and remains in complete remission with no evidence of infection. The incidence of fusariosis in allogeneic-SCT ranges from 0.2% to 0.6% and in acute leukemia from 0.1% to 0.3% [1]. There is an increased incidence of Fusarium infection in immunosuppressed patients and in AML patients compared to other hematological malignancies [2,4]. In an immunocompromised host, lack of a normal immune response allows for angio-invasion of Fusarium, causing necrosis and disseminated infections.