Optimizing antifungal prophylaxis in allogeneic stem cell transplantation: A cohort study of two different approaches.

BACKGROUND: Limited consensus exists on the optimal use of antifungal agents to prevent invasive fungal infection in the early post allogeneic hematopoietic stem cell transplant (alloHCT) period, particularly when patients cannot tolerate oral medication administration. METHODS: We undertook a retrospective observational cohort study to assess the tolerability, efficacy, and cost of a new antifungal prophylaxis pathway at a major tertiary alloHCT centre. Patients aged ≥16 years who underwent alloHCT between February 2018 and October 2019 (cohort 1) or between April 2020 and November 2021 (cohort 2) were included. In both cohorts, first line prophylactic therapy was oral posaconazole. The second line drugs where oral therapy was unable to be administered were intravenous voriconazole (cohort 1) versus intravenous posaconazole (cohort 2). RESULTS: There were 142 patients enrolled in the study, 71 in each cohort. The proportion of patients remaining on first-line prophylaxis or progressing to second-, third-, and fourth-line options was 22.5%, 39.4%, 29.6%, and 8.5% in cohort 1 and 39.4%, 59.2%, 1.4%, and 0% in cohort 2, respectively. The frequency of neuropsychiatric adverse events was significantly higher in cohort 1 compared to cohort 2 (49.3% vs. 19.8%, p = .0004). Occurrence of proven and probable fungal infections was not significantly different between cohorts. Antifungal drug expenditure was $359 935 (AUD) more in cohort 1 ($830 486 AUD) compared to cohort 2 ($477 149 AUD). CONCLUSION: The antifungal prophylaxis pathway used in cohort 2 resulted in reduced antifungal-associated adverse effects, less patients requiring progression to 3rd and 4th line prophylaxis and reduced antifungal drug costs.

Acute myeloid leukaemia relapsing after allogeneic haemopoietic stem cell transplantation: prognostic factors and impact of initial therapy of relapse.

BACKGROUND/AIMS: We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft-versus-host disease (GVHD) on OSR. METHODS: Data on 386 patients from nine Australian centres with relapsed AML post-alloHSCT were collected retrospectively. OSR was calculated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using the log-rank test and proportional hazards modelling, respectively and a prognostic index for OSR was derived from multivariate modelling. RESULTS: On multivariate analysis, relapse within 6 months (hazard ratio (HR) 2.4, P < 0.001) and grade 3-4 acute GVHD preceding relapse (HR 2.0, P = 0.004), were associated with inferior OSR. Patients with 1-2 factors had inferior OSR compared to those with zero factors (all patients: HR 2.3, P < 0.001, patients given salvage: HR 1.8, P < 0.001). The first salvage therapy used post-relapse was donor cell therapy (DCT) (second alloHSCT or donor lymphocyte infusion) in 75, re-induction chemotherapy (CT) in 103, radiotherapy in 8 and interferon-α in 6. Although re-induction CT death rate was low (2%), survival after CT was inferior to DCT (HR 1.9, P < 0.001). No survival benefit was seen for patients who developed GVHD following salvage therapy (P = 0.405). CONCLUSION: Patients with AML who relapse beyond 6 months from alloHSCT without prior grade 3-4 acute GVHD have a better outcome from salvage therapy. Salvage treatments employing DCT as the initial treatment of AML relapse confer a survival advantage over CT.

Targeting Molecular Measurable Residual Disease and Low-Blast Relapse in AML With Venetoclax and Low-Dose Cytarabine: A Prospective Phase II Study (VALDAC).

PURPOSE: A prospective phase II study examined the safety and efficacy of venetoclax combined with low-dose cytarabine (LDAC) in AML at first measurable residual disease (MRD) or oligoblastic relapse. METHODS: Patients with either MRD (≥1 log10 rise) or oligoblastic relapse (blasts 5%-15%) received venetoclax 600 mg once daily D1-28 plus LDAC once daily D1-10 in 28-day cycles. The primary objective was MRD response in the MRD relapse cohort or complete remission (CR/CRh/CRi) in the oligoblastic relapse cohort. RESULTS: Forty-eight adults with either MRD (n = 26) or oligoblastic (n = 22) relapse were enrolled. Median age was 67 years (range, 18-80) and 94% had received previous intensive chemotherapy. Patients received a median of four cycles of therapy; 17% completed ≥12 cycles. Patients with oligoblastic relapse had more grade ≥3 anemia (32% v 4%; P = .02) and infections (36% v 8%; P = .03), whereas grade 4 neutropenia (32 v 23%) or thrombocytopenia (27 v 15%) were comparable with the MRD relapse cohort. Markers of molecular MRD relapse included mutant NPM1 (77%), CBFB::MYH11 (4%), RUNX1::RUNX1T1 (4%), or KMT2A::MLLT3 (4%). Three patients with a log10 rise in IDH1/2 (12%) were included. By cycle 2 in the MRD relapse cohort, a log10 reduction in MRD was observed in 69%; 46% achieved MRD negative remission. In the oligoblastic relapse cohort, 73% achieved CR/CRh/CRi. Overall, 21 (44%) underwent hematopoietic cell transplantation. Median overall survival (OS) was not reached in either cohort. Estimated 2-year OS rate was 67% (95% CI, 50 to 89) in the MRD and 53% (95% CI, 34 to 84) in the oligoblastic relapse cohorts. CONCLUSION: For AML in first remission and either MRD or oligoblastic relapse, venetoclax plus LDAC is well tolerated and highly effective.

How comparable are patient outcomes in the "real-world" with populations studied in pivotal AML trials?

Despite an increasing desire to use historical cohorts as "synthetic" controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012-2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.

The mean fluorescence intensities of anti-HLA antibodies detected using micro-bead flow cytometry predict the risk of platelet transfusion refractoriness.

There are no accepted methods to predict the development of platelet transfusion refractoriness (PTR) due to human leucocyte antigen (HLA)-alloimmunization. Hence, matched platelets are usually given only to patients demonstrating PTR, necessarily resulting in some ineffective random donor platelets (RDPLT) transfusions. To assess its utility in predicting PTR, we retrospectively tested samples from 387 patients receiving chemotherapy for acute leukaemia or autologous transplantation using a micro-bead flow cytometry assay. The average of the mean fluorescence intensities (avgMFI) of the class I beads in the screening assay was correlated with outcomes of RDPLT transfusions during a 2 week period. Antibodies were detected in 57 patients; 66 developed PTR, of whom 28 were alloimmunized. avgMFI usefully predicted the development of PTR (area under the receiver operating curve 0.87, 95% confidence interval: 0.77-0.96). A logistic regression model estimated the probability of PTR to be >90% when avgMFI >5440. These results indicate that micro-bead flow cytometry assays could inform a risk-adapted strategy for managing thrombocytopaenic HLA allo-immunized patients.

An outbreak of fatal pneumonitis caused by contamination of illicit alcohol with paraquat.

INTRODUCTION: We describe a series of unsuspected paraquat poisonings presenting as an outbreak of fatal acute pneumonitis. Exposure to paraquat occurred during the widespread practice of adding substances to alter the taste or potency of illicit alcohol. The diagnosis was suspected only after autopsy findings suggestive of paraquat toxicity were seen in the first fatality. CASE SERIES: An estimated 50 persons were exposed. Of these, 5 presented with ever and progressive dyspnoea, and died 9-30 days after exposure. We were able to trace 35 potentially exposed persons who survived, and compared them to the fatalities. Fever, headache, cough, dyspnoea, abdominal pain, hepatomegaly, and lung signs were more common among those who died. Autopsy revealed widespread renal and hepatic necrosis in the early deaths, and prominent pulmonary fibrosis in those dying later. CONCLUSION: This case series defines an unusual syndrome of paraquat poisoning, which should be considered in the diagnosis of outbreaks of acute pneumonitis in illicit alcohol users.

A Comparison of High-Dose Cytarabine During Induction Versus Consolidation Therapy in Newly Diagnosed AML.

The proportion of patients with acute myeloid leukemia (AML) cured is increased by administering high-dose cytarabine (HiDAC). It remains uncertain whether to administer HiDAC as induction or consolidation, and whether ≥1 cycle of HiDAC is required. Our retrospective study of 416 adult AML patients, excluding good risk cytogenetics, compared a single cycle of HiDAC-based therapy followed by 2 cycles of standard-dose cytarabine (SDAC) (HiDAC induction cohort) with SDAC-based chemotherapy followed by 2 cycles of HiDAC-based chemotherapy (HiDAC consolidation cohort). Complete remission (CR) rate was greater in the HiDAC induction cohort (90% vs 78%, P < 0.01) which did not lead to an improved overall survival (48% vs 43%, P = 0.18) or disease-free survival (DFS) (39% vs 45%, P = 0.95). We noted that, after censoring for allogeneic hematopoetic stem cell transplant (alloHSCT) in CR1, the cumulative incidence of relapse was lower in the HiDAC consolidation cohort in patients with intermediate risk cytogenetics (68% vs 44%, P = 0.01), which lead to a greater DFS (30% vs 47%, P = 0.095). In the patients with adverse risk cytogenetics, the RR was numerically greater in the HiDAC consolidation cohort (52% vs 80%, P = 0.60) which lead to a lower DFS (27% vs 4%, P = 0.11). Our data show that, although the HiDAC induction cohort (1 cycle of HiDAC) achieved a greater CR rate, there were no overall survival differences between the 2 cohorts, and that the HiDAC consolidation cohort (2 cycles of HiDAC) had a lower RR and greater DFS in those patients with intermediate risk cytogenetics who did not undergo alloHSCT in CR1.

Mobilisation strategies for normal and malignant cells.

This review evaluates the latest information on the mobilisation of haemopoietic stem cells for transplantation, with the focus on what is the current best practice and how new understanding of the bone marrow stem cell niche provides new insights into optimising mobilisation regimens. The review then looks at the mobilisation of mesenchymal stromal cells, immune cells as well as malignant cells and what clinical implications there are.