Empiric vs Preemptive Antifungal Strategy in High-Risk Neutropenic Patients on Fluconazole Prophylaxis: A Randomized Trial of the European Organization for Research and Treatment of Cancer.

BACKGROUND: Empiric antifungal therapy is considered the standard of care for high-risk neutropenic patients with persistent fever. The impact of a preemptive, diagnostic-driven approach based on galactomannan screening and chest computed tomography scan on demand on survival and on the risk of invasive fungal disease (IFD) during the first weeks of high-risk neutropenia is unknown. METHODS: Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and allogeneic hematopoietic cell transplant recipients were randomly assigned to receive caspofungin empirically (arm A) or preemptively (arm B), while receiving fluconazole 400 mg daily prophylactically. The primary end point of this noninferiority study was overall survival (OS) 42 days after randomization. RESULTS: Of 556 patients recruited, 549 were eligible: 275 in arm A and 274 in arm B. Eighty percent of the patients had AML or MDS requiring high-dose chemotherapy, and 93% of them were in the first induction phase. At day 42, the OS was not inferior in arm B (96.7%; 95% confidence interval [CI], 93.8%-98.3%) when compared with arm A (93.1%; 95% CI, 89.3%-95.5%). The rates of IFDs at day 84 were not significantly different, 7.7% (95% CI, 4.5%-10.8%) in arm B vs 6.6% (95% CI, 3.6%-9.5%) in arm A. The rate of patients who received caspofungin was significantly lower in arm B (27%) than in arm A (63%; P < .001). CONCLUSIONS: The preemptive antifungal strategy was safe for high-risk neutropenic patients given fluconazole as prophylaxis, halving the number of patients receiving antifungals without excess mortality or IFDs. Clinical Trials Registration. NCT01288378; EudraCT 2010-020814-27.

Expansions of tumor-reactive Vdelta1 gamma-delta T cells in newly diagnosed patients with chronic myeloid leukemia.

Recent studies have underscored the importance of gamma-delta (γδ) T cells in mediating potent MHC-unrestricted cytotoxicity in numerous malignancies. Here, we analyzed Vδ1 and Vδ2 γδ T cell subsets in newly diagnosed chronic myeloid leukemia (CML) patients (n = 40) who had initiated tyrosine kinase inhibitor (TKI) therapy including imatinib (n = 22), nilotinib (n = 14) and dasatinib (n = 4). Patient peripheral blood samples were analyzed at diagnosis and monitored prospectively at 3, 6, 12 and 18 months post-TKI. γδ T cells isolated from healthy donors and CML patients were used against K562, LAMA-84 and KYO-1 cell lines and against primary CML cells in cytotoxicity assays. We found large expansions of Vδ1 and Vδ2 T cells in patients at diagnosis compared to age-matched healthy donors (n = 40) (p < 0.0001). The γδ T cell reconstitution in patients on imatinib and also on nilotinib showed significant reductions of Vδ1 T cell and Vδ2 T cell absolute counts at 3 months compared to diagnosis. Importantly, Vδ1 and Vδ2 T absolute cell counts remained at normal levels from 3 months throughout the follow-up. Next, we observed susceptibility to specific lysis of primary CML tumor cells by Vδ1 T cells from healthy donors. Furthermore, we determined inherent cytotoxic reactivity by autologous patients' Vδ1 T lymphocytes against primary CML tumor cells. Finally, the TCR clonality profiles showed in CML patients mostly polyclonal repertoires regardless of the TKI. Our results provide further evidence into γδ T cell antileukemia immunity in CML that might be beneficial for long-term disease control and treatment outcome.

COVID-19 in adult acute myeloid leukemia patients: a long-term follow-up study from the European Hematology Association survey (EPICOVIDEHA).

Patients with acute myeloid leukemia (AML) are at high risk of dying from coronavirus disease 2019 (COVID-19). The optimal management of AML patients with COVID-19 has not been established. Our multicenter study included 388 adult AML patients diagnosed with COVID-19 between February 2020 and October 2021. The vast majority were receiving or had received AML treatment in the preceding 3 months. COVID-19 was severe in 41.2% and critical in 21.1% of cases. The chemotherapeutic schedule was modified in 174 patients (44.8%), delayed in 68 and permanently discontinued in 106. After a median follow-up of 325 days, 180 patients (46.4%) had died; death was attributed to COVID-19 (43.3%), AML (26.1%) or to a combination of both (26.7%), whereas in 3.9% of cases the reason was unknown. Active disease, older age, and treatment discontinuation were associated with death, whereas AML treatment delay was protective. Seventy-nine patients had a simultaneous AML and COVID-19 diagnosis, with better survival when AML treatment could be delayed (80%; P<0.001). Overall survival in patients with a diagnosis of COVID-19 between January 2020 and August 2020 was significantly lower than that in patients diagnosed between September 2020 and February 2021 and between March 2021 and September 2021 (39.8% vs. 60% vs. 61.9%, respectively; P=0.006). COVID-19 in AML patients was associated with a high mortality rate and modifications of therapeutic algorithms. The best approach to improve survival was to delay AML treatment, whenever possible.

Clinical features and prognostic factors of Magnusiomyces (Saprochaete) infections in haematology. A multicentre study of SEIFEM/Fungiscope.

BACKGROUND: Our multicentre study aims to identify baseline factors and provide guidance for therapeutic decisions regarding Magnusiomyces-associated infections, an emerging threat in patients with haematological malignancies. METHODS: HM patients with proven (Magnusiomyces capitatus) M. capitatus or (Magnusiomyces clavatus) M. clavatus (formerly Saprochaete capitata and Saprochaete clavata) infection diagnosed between January 2010 and December 2020 were recorded from the SEIFEM (Sorveglianza Epidemiologica Infezioni nelle Emopatie) group and FungiScope (Global Emerging Fungal Infection Registry). Cases of Magnusiomyces fungemia were compared with candidemia. RESULTS: Among 90 Magnusiomyces cases (60 [66%] M. capitatus and 30 (34%) M. clavatus), median age was 50 years (range 2-78), 46 patients (51%) were female and 67 (74%) had acute leukaemia. Thirty-six (40%) of Magnusiomyces-associated infections occurred during antifungal prophylaxis, mainly with posaconazole (n = 13, 36%) and echinocandins (n = 12, 34%). Instead, the candidemia rarely occurred during prophylaxis (p < .0001). First-line antifungal therapy with azoles, alone or in combination, was associated with improved response compared to other antifungals (p = .001). Overall day-30 mortality rate was 43%. Factors associated with higher mortality rates were septic shock (HR 2.696, 95% CI 1.396-5.204, p = .003), corticosteroid treatment longer than 14 days (HR 2.245, 95% CI 1.151-4.376, p = .018) and lack of neutrophil recovery (HR 3.997, 95% CI 2.102-7.601, p < .001). The latter was independently associated with poor outcome (HR 2.495, 95% CI 1.192-5.222, p = .015). CONCLUSIONS: Magnusiomyces-associated infections are often breakthrough infections. Effective treatment regimens of these infections remain to be determined, but neutrophil recovery appears to play an important role in the favourable outcome.

Invasive Trichoderma spp. infections: clinical presentation and outcome of cases from the literature and the FungiScope® registry.

BACKGROUND: Trichoderma spp. are filamentous fungi causing invasive fungal diseases in patients with haematological malignancies and in peritoneal dialysis patients. OBJECTIVES: To analyse clinical presentation, predisposing factors, treatment and outcome of Trichoderma infections. METHODS: A systematic literature review was conducted for published cases of invasive Trichoderma infection in PubMed until December 2021 and by reviewing the included studies' references. Cases from the FungiScope® registry were added to a combined analysis. RESULTS: We identified 50 invasive infections due to Trichoderma species, including 11 in the FungiScope® registry. The main underlying conditions were haematological malignancies in 19 and continuous ambulatory peritoneal dialysis (CAPD) in 10 cases. The most prevalent infection sites were lung (42%) and peritoneum (22%). Systemic antifungal therapy was administered in 42 cases (84%), mostly amphotericin B (n = 27, lipid-based formulation 13/27) and voriconazole in 15 cases (30%). Surgical interventions were performed in 13 cases (26%). Overall mortality was 48% (n = 24) and highest for allogeneic HSCT and solid organ transplantation (SOT) recipients [80% (4/5) and 77% (7/9), respectively]. In patients treated with amphotericin B, voriconazole and caspofungin, mortality was 55% (15/27), 46% (7/15) and 28% (2/7), respectively. Three out of four patients treated with a combination therapy of voriconazole and caspofungin survived. CONCLUSIONS: Despite treatment with antifungal therapies and surgery, invasive Trichoderma infections are life-threatening complications in immunocompromised patients, especially after HSCT and SOT. In addition, Trichoderma spp. mainly affect the lungs in patients with haematological malignancies and the peritoneum in CAPD patients.

Characteristics and outcome of patients with core-binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study.

The aim of this study was to evaluate the prognostic impact of FLT3-ITD in core-binding factor acute myeloid leukemia (CBFAML) in an international, multicenter survey of 97 patients of whom 52% had t(8;21)(q22;q22) and 48% had inv(16)(p13q22)/t(16;16)(p13;q22). The median age of the patients was 53 years (range, 19-81). Complete remission after anthracycline-based induction (n=86) and non-intensive therapy (n=11) was achieved in 97% and 36% of the patients, respectively. The median follow-up was 4.43 years (95% confidence interval [95% CI]: 3.35-7.39 years). The median survival after intensive and non-intensive treatment was not reached and 0.96 years, respectively. Among intensively treated patients, inv(16) with trisomy 22 (n=11) was associated with a favorable 4-year relapse-free survival rate of 80% (95% CI: 59-100%) as compared to 38% (95% CI: 27-54%; P=0.02) in all other patients with CBFAML/ FLT3-ITD (n=75). Overall, 24 patients underwent allogeneic hematopoietic cell transplantation (HCT), 12 in first complete remission and 12 after relapse. Allogeneic HCT in first complete remission was not beneficial (P=0.60); however, allogeneic HCT seemed to improve median survival in relapsed patients compared to that of patients treated with chemotherapy (not reached vs. 0.6 years, respectively; P=0.002). Excluding patients with inv(16) with trisomy 22, our data indicate that compathe outcome of CBF-AML patients with FLT3-ITD may be inferior to that of patients without FLT3-ITD (based on previously published data), suggesting that prognostically CBF-AML patients with FLT3-ITD should not be classified as favorable-risk. FLT3-inhibitors may improve the outcome of these patients.

Hierarchical distribution of somatic variants in newly diagnosed chronic myeloid leukaemia at diagnosis and early follow-up.

There is an emerging body of evidence that patients with chronic myeloid leukaemia (CML) may carry not only breakpoint cluster region-Abelson murine leukaemia viral oncogene homologue 1 (BCR-ABL1) kinase domain mutations (BCR-ABL1 KD mutations), but also mutations in other genes. Their occurrence is highest during progression or at failure, but their impact at diagnosis is unclear. In the present study, we prospectively screened for mutations in 18 myeloid neoplasm-associated genes and BCR-ABL1 KD in the following populations: bulk leucocytes, CD34+ CD38+ progenitors and CD34+ CD38- stem cells, at diagnosis and early follow-up. In our cohort of chronic phase CML patients, nine of 49 patients harboured somatic mutations in the following genes: six ASXL1 mutations, one SETBP1, one TP53, one JAK2, but no BCR-ABL1 KD mutations. In seven of the nine patients, mutations were detected in multiple hierarchical populations including bulk leucocytes at diagnosis. The mutation dynamics reflected the BCR-ABL1 transcript decline induced by treatment in eight of the nine cases, suggesting that mutations were acquired in the Philadelphia chromosome (Ph)-positive clone. In one patient, the JAK2 V617F mutation correlated with a concomitant Ph-negative myeloproliferative neoplasm and persisted despite a 5-log reduction of the BCR-ABL1 transcript. Only two of the nine patients with mutations failed first-line therapy. No correlation was found between the mutation status and survival or response outcomes.

Characteristics and outcome of patients with acute myeloid leukaemia and t(8;16)(p11;p13): results from an International Collaborative Study.

In acute myeloid leukaemia (AML) t(8;16)(p11;p13)/MYST3-CREBBP is a very rare abnormality. Previous small series suggested poor outcome. We report on 59 patients with t(8;16) within an international, collaborative study. Median age was 52 (range: 16-75) years. AML was de novo in 58%, therapy-related (t-AML) in 37% and secondary after myelodysplastic syndrome (s-AML) in 5%. Cytogenetics revealed a complex karyotype in 43%. Besides MYST3-CREBBP, whole-genome sequencing on a subset of 10 patients revealed recurrent mutations in ASXL1, BRD3, FLT3, MLH1, POLG, TP53, SAMD4B (n = 3, each), EYS, KRTAP9-1 SPTBN5 (n = 4, each), RUNX1 and TET2 (n = 2, each). Complete remission after intensive chemotherapy was achieved in 84%. Median follow-up was 5·48 years; five-year survival rate was 17%. Patients with s-/t-AML (P = 0·01) and those with complex karyotype (P = 0·04) had an inferior prognosis. Allogeneic haematopoietic cell transplantation (allo-HCT) was performed in 21 (36%) patients, including 15 in first complete remission (CR1). Allo-HCT in CR1 significantly improved survival (P = 0·04); multivariable analysis revealed that allo-HCT in CR1 was effective in de novo AML but not in patients with s-AML/t-AML and less in patients exhibiting a complex karyotype. In summary, outcomes of patients with t(8;16) are dismal with chemotherapy, and may be substantially improved with allo-HCT performed in CR1.

Invasive infections with Purpureocillium lilacinum: clinical characteristics and outcome of 101 cases from FungiScope® and the literature.

OBJECTIVES: To provide a basis for clinical management decisions in Purpureocillium lilacinum infection. METHODS: Unpublished cases of invasive P. lilacinum infection from the FungiScope® registry and all cases reported in the literature were analysed. RESULTS: We identified 101 cases with invasive P. lilacinum infection. Main predisposing factors were haematological and oncological diseases in 31 cases (30.7%), steroid treatment in 27 cases (26.7%), solid organ transplant in 26 cases (25.7%), and diabetes mellitus in 19 cases (18.8%). The most prevalent infection sites were skin (n = 37/101, 36.6%) and lungs (n = 26/101, 25.7%). Dissemination occurred in 22 cases (21.8%). Pain and fever were the most frequent symptoms (n = 40/101, 39.6% and n = 34/101, 33.7%, respectively). Diagnosis was established by culture in 98 cases (97.0%). P. lilacinum caused breakthrough infection in 10 patients (9.9%). Clinical isolates were frequently resistant to amphotericin B, whereas posaconazole and voriconazole showed good in vitro activity. Susceptibility to echinocandins varied considerably. Systemic antifungal treatment was administered in 90 patients (89.1%). Frequently employed antifungals were voriconazole in 51 (56.7%) and itraconazole in 26 patients (28.9%). Amphotericin B treatment was significantly associated with high mortality rates (n = 13/33, 39.4%, P = <0.001). Overall mortality was 21.8% (n = 22/101) and death was attributed to P. lilacinum infection in 45.5% (n = 10/22). CONCLUSIONS: P. lilacinum mainly presents as soft-tissue, pulmonary or disseminated infection in immunocompromised patients. Owing to intrinsic resistance, accurate species identification and susceptibility testing are vital. Outcome is better in patients treated with triazoles compared with amphotericin B formulations.

Early and late stage MPN patients show distinct gene expression profiles in CD34+ cells.

Myeloproliferative neoplasms (MPN), comprising essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are hematological disorders of the myeloid lineage characterized by hyperproliferation of mature blood cells. The prediction of the clinical course and progression remains difficult and new therapeutic modalities are required. We conducted a CD34+ gene expression study to identify signatures and potential biomarkers in the different MPN subtypes with the aim to improve treatment and prevent the transformation from the rather benign chronic state to a more malignant aggressive state. We report here on a systematic gene expression analysis (GEA) of CD34+ peripheral blood or bone marrow cells derived from 30 patients with MPN including all subtypes (ET (n = 6), PV (n = 11), PMF (n = 9), secondary MF (SMF; post-ET-/post-PV-MF; n = 4)) and six healthy donors. GEA revealed a variety of differentially regulated genes in the different MPN subtypes vs. controls, with a higher number in PMF/SMF (200/272 genes) than in ET/PV (132/121). PROGENγ analysis revealed significant induction of TNFα/NF-κB signaling (particularly in SMF) and reduction of estrogen signaling (PMF and SMF). Consistently, inflammatory GO terms were enriched in PMF/SMF, whereas RNA splicing-associated biological processes were downregulated in PMF. Differentially regulated genes that might be utilized as diagnostic/prognostic markers were identified, such as AREG, CYBB, DNTT, TIMD4, VCAM1, and S100 family members (S100A4/8/9/10/12). Additionally, 98 genes (including CLEC1B, CMTM5, CXCL8, DACH1, and RADX) were deregulated solely in SMF and may be used to predict progression from early to late stage MPN.

Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.

BACKGROUND: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. METHODS: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. RESULTS: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. CONCLUSIONS: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

Novel Illumina-based next generation sequencing approach with one-round amplification provides early and reliable detection of BCR-ABL1 kinase domain mutations in chronic myeloid leukemia.

The occurrence of mutations in the BCR-ABL1 kinase domain (KD) can lead to treatment resistance in chronic myeloid leukaemia patients. Nowadays, next-generation sequencing (NGS) is an alternative method for the detection of kinase domain mutations, compared to routinely used Sanger sequencing, providing a higher sensitivity of mutation detection. However, in the protocols established so far multiple rounds of amplification limit reliable mutation detection to approximately 5% variant allele frequency. Here, we present a simplified, one-round amplification NGS protocol for the Illumina platform, which offers a robust early detection of BCR-ABL1 KD mutations with a reliable detection limit of 3% variant allele frequency.

Clonal hierarchy of main molecular lesions in acute myeloid leukaemia.

Genetic mutations in acute myeloid leukaemia (AML) are assumed to occur in a sequential order; however, the predominant hierarchical roles of specific mutated genes have not been fully described. In this study, we aimed to determine the clonal involvement of the most frequent AML-associated mutations. Using a targeted sequencing panel for 18 genes, we traced changes and relative clonal contribution of mutations in 52 patients. We analysed 35 pairs of diagnosis and relapse samples, 27 pairs of primary samples and corresponding patient-derived xenografts, and 34 pairs of total leukocytes and corresponding isolated primitive cells or blast populations. In both relapse and xenografts, we observed conservation of main leukaemic clones and variability was limited to subclones with late-acquired mutations. AML evolution thus mainly involved modification of subclones while the clonal background remained unchanged. NPM1 mutations were identified as the most probable leukaemia-transformation lesion, remaining conserved in contrast to high variation of accompanying subclonal FLT3 and NRAS mutations. DNMT3A mutations represented the most stable mutations forming a preleukaemic background in most samples. Mutations in genes IDH1/2, TET2, RUNX1, ASXL1 and U2AF1 were detected both as preleukaemic and as subclonal lesions, suggesting a non-specific order of acquisition.

Allogeneic hematopoietic cell transplantation improves outcome of adults with t(6;9) acute myeloid leukemia: results from an international collaborative study.

Acute myeloid leukemia (AML) with t(6;9)(p22;q34) is a distinct entity accounting for 1-2% of AML cases. A substantial proportion of these patients have a concomitant FLT3-ITD. While outcomes are dismal with intensive chemotherapy, limited evidence suggests allogeneic hematopoietic cell transplantation (allo-HCT) may improve survival if performed early during first complete remission. We report on a cohort of 178 patients with t(6;9)(p22;q34) within an international, multicenter collaboration. Median age was 46 years (range: 16-76), AML was de novo in 88%, FLT3-ITD was present in 62%, and additional cytogenetic abnormalities in 21%. Complete remission was achieved in 81% (n=144), including 14 patients who received high-dose cytarabine after initial induction failure. With a median follow up of 5.43 years, estimated overall survival at five years was 38% (95%CI: 31-47%). Allo-HCT was performed in 117 (66%) patients, including 89 in first complete remission. Allo-HCT in first complete remission was associated with higher 5-year relapse-free and overall survival as compared to consolidation chemotherapy: 45% (95%CI: 35-59%) and 53% (95%CI: 42-66%) versus 7% (95%CI: 3-19%) and 23% (95%CI: 13-38%), respectively. For patients undergoing allo-HCT, there was no difference in overall survival rates at five years according to whether it was performed in first [53% (95%CI: 42-66%)], or second [58% (95%CI: 31-100%); n=10] complete remission or with active disease/relapse [54% (95%CI: 34-84%); n=18] (P=0.67). Neither FLT3-ITD nor additional chromosomal abnormalities impacted survival. In conclusion, outcomes of t(6;9)(p22;q34) AML are poor with chemotherapy, and can be substantially improved with allo-HCT.

Prognostic significance of mutation profile at diagnosis and mutation persistence during disease remission in adult acute myeloid leukaemia patients.

In this multi-centre study, we analysed the prognostic impact of mutations in 19 genes associated with myeloid malignancies in 258 newly diagnosed acute myeloid leukaemia patients (aged 19-70 years) undergoing intensive therapy. We identified five patient groups with different prognostic risks and different benefits from allogeneic hematopoietic stem cell transplantation (alloHSCT) within the intermediate cytogenetic risk group patients (n = 184). The most adverse prognosis was observed in patients with DNMT3A and FLT3-ITD co-mutation, whose survival could be significantly improved with alloHSCT. In contrast, the most favourable prognosis without any further benefit from alloHSCT was identified in patients with mutations in NPM1 or CEBPA, after exclusion of the unfavourable prognostic groups defined by mutations in DNMT3A, RUNX1 or genes from chromatin/spliceosome group. An additional analysis of 113 diagnosis-remission paired samples revealed that persistence of non-DNMT3A mutations (above 2% VAF) represented a further negative prognostic factor. The proposed model offers a possible molecular stratification and treatment guidance for intermediate cytogenetic risk group patients.

Matched-paired analysis of patients treated for invasive mucormycosis: standard treatment versus posaconazole new formulations (MoveOn).

BACKGROUND: First-line antifungal treatment for invasive mucormycosis (IM) consists of liposomal amphotericin B. Salvage treatment options are limited and often based on posaconazole oral suspension. With the approval of posaconazole new formulations, patients could benefit from improved pharmacokinetics, safety and tolerability. OBJECTIVES: Our aim was to assess the effectiveness of posaconazole new formulations for IM treatment. METHODS: We performed a case-matched analysis with proven or probable IM patients from the FungiScope® Registry. First-line posaconazole new formulations (1st-POSnew) and first-line amphotericin B plus posaconazole new formulations (1st-AMB+POSnew) cases were matched with first-line amphotericin B-based (1st-AMB) treatment controls. Salvage posaconazole new formulations (SAL-POSnew) cases were matched with salvage posaconazole oral suspension (SAL-POSsusp) controls. Each case was matched with up to three controls (based on severity, haematological/oncological malignancy, surgery and/or renal dysfunction). RESULTS: Five patients receiving 1st-POSnew, 18 receiving 1st-AMB+POSnew and 22 receiving SAL-POSnew were identified. By day 42, a favourable response was reported for 80.0% (n = 4/5) of patients receiving 1st-POSnew, for 27.8% (n = 5/18) receiving 1st-AMB+POSnew and for 50.0% (n = 11/22) receiving SAL-POSnew. Day 42 all-cause mortality of patients receiving posaconazole new formulations was lower compared with controls [20.0% (n = 1/5) in 1st-POSnew versus 53.3% (n = 8/15) in 1st-AMB; 33.3% (n = 6/18) in 1st-AMB+POSnew versus 52.0% (n = 26/50) in 1st-AMB; and 0.0% (n = 0/22) in SAL-POSnew versus 4.4% (n = 2/45) in SAL-POSsusp]. CONCLUSIONS: Posaconazole new formulations were effective in terms of treatment response and associated mortality of IM. While posaconazole new formulations may be an alternative for treatment of IM, the limited sample size of our study calls for a cautious interpretation of these observations.