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The distribution of genetic mutations affects seven out of 20 patients (35%), mainly related to I TP53 i (six patients, 30%), I TET2 i (two patients, 10%) and I DNMT3A i (two patients, 10%). During the long-term follow-ups of randomized controlled trials (RCTs), some cases of therapy-associated myeloid neoplasms (t-MNs), including myelodysplastic syndrome (t-MDS) and acute myeloid leukaemia (t-AML), were reported both in the poly(ADP-ribose)polymerase inhibitors (PARPi) and control arms. For the 21 patients, t-MNs occurred after a median latency period of 18-2 (IQR 10-0-30-0) months following first PARPi exposure. Among them, 113 out of 32 662 patients (0-3%) with OC experienced t-MNs after a mean time from first primary cancer diagnosis of 5-3 years for t-MDS ( I n i = 47 patients) and 4-5 years for t-AML ( I n i = 66 patients), with an overall standardized incidence ratio of 5-8 (4-8-6-9).8 Our shorter latency may be linked to an underlying clonal haematopoiesis as I TET2 i and I DNMT3A i mutations were frequently found. [Extracted from the article]

Summary: Primary objective of this non‐interventional, post‐authorisation safety study was to provide real‐world safety data [incidence of adverse drug reactions (ADRs)/serious adverse events (SAEs)] on adult patients with myelofibrosis exposed/or not exposed to ruxolitinib. Key secondary objectives included the incidence/outcome of events of special interest (bleeding events, serious/opportunistic infections, second primary malignancies, and deaths). Overall, 462 patients were included [prevalent users = 260, new users = 32, non‐exposed = 170 (inclusive of ruxolitinib‐switch, n = 57)]. The exposure‐adjusted incidence rates (per 100 patient‐years) of ADRs (19·3 vs. 19·6) and SAEs (25·2 vs. 25·0) were comparable amongst new‐users versus prevalent‐users cohorts, respectively; most frequent ADRs across all cohorts included thrombocytopenia, anaemia, epistaxis, urinary tract infection, and herpes zoster. Anaemia, pneumonia, general physical health deterioration, sepsis, and death were the most frequent SAEs across all cohorts. Incidence rates of bleeding events (21·6) and serious/opportunistic infections (34·5) were higher in ruxolitinib‐switch cohort versus other cohorts. The incidence rate of second primary malignancies was higher in the prevalent‐users cohort (10·1) versus other cohorts. The observed safety profile of ruxolitinib in the present study along with the safety findings from the COMFORT/JUMP/EXPAND studies support the use of ruxolitinib for long‐term treatment of patients with myelofibrosis. [ABSTRACT FROM AUTHOR]

Summary: Objectives: Invasive fungal infections caused by Lomentospora prolificans are associated with very high mortality rates and can be challenging to treat given pan‐drug resistance to available antifungal agents. The objective of this study was to describe the clinical presentation and outcomes in a cohort of patients with invasive L prolificans infections. Methods: We performed a retrospective review of medical records of patients with invasive L prolificans infection in the FungiScope® registry of rare invasive fungal infections. Patients diagnosed between 01 January 2008 and 09 September 2019 were included in for analysis. Results: The analysis included 41 patients with invasive L prolificans infection from eight different countries. Haematological/oncological malignancies were the most frequent underlying disease (66%), disseminated infection was frequent (61%), and the lung was the most commonly involved organ (44%). Most infections (59%) were breakthrough infections. Progression/deterioration/treatment failure was observed in 23/40 (58%) of patients receiving antifungal therapy. In total, 21/41 (51%) patients, and 77% of patients with underlying haematological/oncological malignancy, had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was frequent (24/40) and associated with improved survival. In particular, treatment regimens including terbinafine were significantly associated with higher treatment success at final assessment (P =.012), with a positive trend observed for treatment regimens that included voriconazole (P =.054). Conclusions: Lomentospora prolificans infections were associated with mortality rates of 77% and above in patients with underlying haematological/oncological malignancies and those with disseminated infections. While combination therapy is the preferred option for now, the hope lies with novel antifungals currently under development. [ABSTRACT FROM AUTHOR]

Summary: Background: The new Rasamsonia spp. complex can develop invasive infection in immunosuppression or chronic pulmonary disease. It has potential to be misidentified as other genera due to morphological similarities. Nowadays, there is a gap of knowledge on this fungi. Objectives: To provide knowledge base of risk factors and therapeutic decisions in invasive Rasamsonia spp. complex infection. Patients/Methods: Cases of invasive infection due to Rasamsonia spp. (formerly Geosmithia/Penicillium spp.) from FungiScope® registry and all reported cases from a literature were included. Results: We identified 23 invasive infections due to Rasamsonia spp., six (26.1%) in the FungiScope® registry. Main risk factors were chronic granulomatous disease (n = 12, 52.2%), immunosuppressive treatment (n = 10, 43.5%), haematopoietic stem cell transplantation (n = 7, 30.4%), graft‐versus‐host disease and major surgery (n = 4, 17.4%, each). Predominantly affected organs were the lungs (n = 21, 91.3%), disease disseminated in seven cases (30.4%). Fungal misidentification occurred in 47.8% (n = 11), and sequencing was used in 69.6% of the patients (n = 16) to diagnose. Breakthrough infection occurred in 13 patients (56.5%). All patients received antifungal treatment, mostly posaconazole (n = 11), caspofungin (n = 10) or voriconazole (n = 9). Combination therapy was administered in 13 patients (56.5%). Susceptibility testing showed high minimum inhibitory concentrations for azoles and amphotericin B, but not for echinocandins. No preferable treatment influencing favourable outcome was identified. Overall mortality was 39% (n = 9). Conclusion: Rasamsonia spp. are emerging fungi causing life‐threatening infections, especially in immunocompromised and critically ill patients. Mortality is high. Treatment is challenging and clinicians dealing with this patient population should become aware of this infection constituting a medical emergency. [ABSTRACT FROM AUTHOR]

Nine of 13 (70%) MLPA-detected ex1 samples displayed exon 1 levels at half those of healthy donors, similar to samples with single I IKZF1 i copies. Both alleles were mutated (a complete deletion and a 5' deletion) in Patient 6; here, IKAROS expression was completely lost in most cells, though some cells retained intermediate IKAROS levels, suggesting clonal heterogeneity. To determine if the 5' deletions affect mRNA expression, I IKZF1 i mRNA levels from 7 ex1-only patients were compared with those of patients with different I IKZF1 i status (wildtype [WT], mono- and biallelic deletions) by reverse transcription-qPCR, using primers to amplify exons 4-5 (Fig C). One common single nucleotide polymorphism (SNP) (rs61731355; C->A at position Chr7:50,400,069 within exon 8) was detected in the gDNA and mRNA (cDNA) of 2 control patients, showing that I IKZF1 i is biallelically expressed in BCP-ALL cells (Fig D). [Extracted from the article]

Summary: Treatment outcomes in patients with proven/probable vs possible invasive mould disease (IMD; 2008 European Organisation for Research and Treatment of Cancer/Mycoses Study Group [EORTC/MSG] criteria) needed further assessment. The Phase III SECURE trial compared isavuconazole vs voriconazole for treatment of IMD. This post hoc analysis assessed all‐cause mortality (ACM) through day 42 (primary endpoint) and day 84, overall and clinical success at end of treatment (EOT), and drug‐related treatment‐emergent adverse events (TEAEs) in subgroups with proven/probable or possible IMD. Of 516 randomised patients, 304 (58.9%) had proven/probable IMD and 164 (31.8%) had possible IMD as per EORTC/MSG criteria; 48 did not have IMD. Across treatment groups, day 42 and day 84 ACM were numerically lower for possible vs proven/probable IMD (day 42: 17.1% vs 21.1%; P = 0.3, day 84: 26.2% vs 32.6%; P = 0.15). Overall and clinical success at EOT were significantly higher for possible IMD compared with proven/probable IMD (48.2% vs 36.2%; P = 0.01, 75.0% vs 63.1%; P = 0.01 respectively). Fewer drug‐related TEAEs were reported with isavuconazole compared with voriconazole in patients with either proven/probable or possible IMD. Compared with patients with proven/probable IMD, those with possible IMD demonstrated higher overall and clinical success rates, supporting early initiation of antifungal treatment. [ABSTRACT FROM AUTHOR]

Acute promyelocytic leukaemia and COVID-19 are two conditions associated with severe coagulopathy. Chest computed tomography (CT) was consistent with moderate COVID-19 pneumonia (nine points on a 0-25 scale).[1] The quantitative reverse transcription polymerase chain reaction (qRT-PCR) of a nasopharyngeal swab was positive for SARS-CoV-2. Computed tomography (CT) angiography showed left middle cerebral artery occlusion (Fig 1). [Extracted from the article]

Cladophialophora bantiana brain abscesses are rare, but are frequently and quickly lethal in transplanted patients. We report the case of a 63-year-old man who had undergone lung transplantation for chronic obstructive pulmonary disease and presented with headaches and a neurological deficit. Magnetic resonance imaging revealed multiple brain abscesses. C. bantiana was identified by DNA sequencing performed directly on cerebral tissue obtained by surgical biopsy. After 6 months of antifungal treatment, the brain abscesses were replaced by ischemic sequelae. The patient died suddenly 2 months later from a pulmonary bacterial infection. This is the second reported case of C. bantiana brain abscesses in a lung transplant recipient, to our knowledge, who experienced a long survival period with medical antifungal treatment alone. We review the literature and discuss our treatment. [ABSTRACT FROM AUTHOR]

Rare invasive fungal diseases ( IFD) are challenging for the treating physicians because of their unspecific clinical presentation, as well as the lack of standardised diagnostic and effective treatment strategies. Late onset of treatment and inappropriate medication is associated with high mortality, thus, urging the need for a better understanding of these diseases. The purpose of FungiScope™ is to continuously collect clinical information and specimens to improve the knowledge on epidemiology and eventually improve patient management of these orphan diseases. FungiScope™ was founded in 2003, and today, collaborators from 66 countries support the registry. So far, clinical data of 794 cases have been entered using a web-based approach. Within the growing network of experts, new collaborations developed, leading to several publications of comprehensive analyses of patient subgroups identified from the registry. Data extracted from FungiScope™ have also been used as the sole control group for the approval of a new antifungal drug. Due to the rarity of these diseases, a global registry is an appropriate method of pooling the scarce and scattered information. Joining efforts across medical specialities and geographical borders is key for researching rare IFD. Here, we describe the structure and management of the FungiScope™ registry. [ABSTRACT FROM AUTHOR]

Patients with mantle cell lymphoma ( MCL) generally respond to first-line immunochemotherapy, but often show chemoresistance upon subsequent relapses, with poor outcome. Several studies of the immunomodulator, lenalidomide, have demonstrated its activity in MCL including the MCL-001 study in relapsed/refractory patients who had failed defined prior therapies of anthracyclines or mitoxantrone, cyclophosphamide, rituximab and also bortezomib. We present here the long-term efficacy follow-up of the prospective phase II MCL-001 study ( N = 134), including new exploratory analyses with baseline Ki-67 ( MIB1), a biological marker of tumour proliferation. With longer follow-up, lenalidomide showed a 28% overall response rate [ ORR; 8% complete response ( CR)/ CR unconfirmed ( CRu)]. Median duration of response ( DOR), progression-free survival and overall survival were 16·6, 4·0 and 20·9 months, respectively. Myelosuppression continued to be the most common grade 3/4 toxicity. Several studies of MCL patients treated with chemotherapy, rituximab and bortezomib have shown an inverse association between survival and Ki-67. Ki-67 data in 81/134 MCL-001 patients showed similar ORRs in both low (<30% or <50%) versus high (≥30% or ≥50%) Ki-67-expressing groups, yet lower Ki-67 levels demonstrated superior CR/ CRu, DOR and survival outcomes. Overall, lenalidomide showed durable efficacy with a consistent safety profile in heavily pretreated, relapsed/refractory MCL post-bortezomib. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis remains associated with significant morbidity and mortality, necessitating new options for salvage therapy. The objective of this study was to evaluate the efficacy and safety of micafungin as salvage monotherapy in patients with invasive aspergillosis. Patients with proven or probable invasive aspergillosis, who were refractory or intolerant to previous systemic antifungal therapy, were randomised 2 : 1 to receive 300 mg day-1 intravenous micafungin monotherapy or an intravenous control monotherapy [lipid amphotericin B (5 mg kg-1 day-1), voriconazole (8 mg kg-1 day-1) or caspofungin (50 mg day-1)] for 3-12 weeks. Patients underwent final assessment 12 weeks after treatment start. Seventeen patients with invasive aspergillosis (proven, n = 2; probable, n = 14; not recorded, n = 1) participated in the study (micafungin arm, n = 12; control arm, n = 5). Three patients each in the micafungin (25.0%; 95% CI: 5.5-57.2) and control arm (60.0%; 95% CI: 14.7-94.7) had successful therapy at end of treatment as assessed by an Independent Data Review Board. Eleven patients died; six due to invasive aspergillosis. No deaths were considered related to study treatment. During this study it became increasingly common to use combination treatment for salvage therapy. Consequently, enrolment was low and the study was discontinued early. No clear trends in efficacy and safety can be concluded. [ABSTRACT FROM AUTHOR]

Severe prolonged neutropenia, allogeneic hematopoietic stem cell or solid-organ transplantation, corticosteroids or other T cell suppressive agents, and other severe immunosuppressive factors have for many years been considered to predispose patients to invasive aspergillosis. Other conditions such as impaired innate immunity, diabetes, renal impairment, progression of the underlying malignancy, prior respiratory disease, and nosocomial or environmental exposure to fungal spores or climatic factors have recently been considered additional risk factors of invasive aspergillosis. The multiplicity of risk factors as well as the obvious synergy between them renders risk stratification difficult. An international, large-scale, multicenter, epidemiological study is necessary to develop a risk score. [ABSTRACT FROM AUTHOR]

The efficacy of bendamustine versus chlorambucil in a phase III trial of previously untreated patients with Binet stage B/C chronic lymphocytic leukaemia ( CLL) was re-evaluated after a median observation time of 54 months in May 2010. Overall survival ( OS) was analysed for the first time. At follow-up, investigator-assessed complete response ( CR) rate (21·0% vs 10·8%), median progression-free survival (21·2 vs 8·8 months; P < 0·0001; hazard ratio 2·83) and time to next treatment (31·7 vs 10·1 months; P < 0·0001) were improved for bendamustine over chlorambucil. OS was not different between groups for all patients or those ≤65 years, >65 years, responders and non-responders. However, patients with objective response or a CR experienced a significantly longer OS than non-responders or those without a CR. Significantly more patients on chlorambucil progressed to second/further lines of treatment compared with those on bendamustine (78·3% vs 63·6%; P = 0·004). The benefits of bendamustine over chlorambucil were achieved without reducing quality of life. In conclusion, bendamustine is significantly more effective than chlorambucil in previously untreated CLL patients, with the achievement of a CR or objective response appearing to prolong OS. Bendamustine should be considered as a preferred first-line option over chlorambucil for CLL patients ineligible for fludarabine, cyclophosphamide and rituximab. [ABSTRACT FROM AUTHOR]

Summary In 2008, the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) published revised definitions for diagnosing invasive fungal disease. A previous prospective trial of liposomal amphotericin B for invasive mould disease (AmBiLoad) used modified EORTC/MSG 2002 criteria. We wished to re-evaluate the response and survival based on the revised definitions to compare the outcomes of early vs. late treatment. Patients who had received an allogeneic haematopoietic stem cell transplant or who were neutropaenic (absolute neutrophil count <500 μl−1 within 14 days of study entry) had been recruited on the basis of a halo or air crescent sign on chest computerised tomography. Originally classified as probable invasive mould disease, they were categorised as possible invasive mould disease using 2008 criteria. Patients had received liposomal amphotericin B at either 3 or 10 mg kg−1 QD for 14 days, followed by 3 mg kg−1 QD. Response at end of treatment and the 12-week survival were re-calculated according to 2008 definitions. Six-week survival was estimated by Kaplan-Meier analysis. Of 201 patients with invasive mould disease, 118 (59%) had a diagnosis based on halo signs (possible cases). Mycological evidence was present in 83 (41%) cases (probable/proven cases). Survival rates at 12 weeks for possible vs. probable/proven cases in the 3 mg kg−1 QD group were 82% vs. 58% ( P = 0.006), and 65% vs. 50% ( P = 0.15) in the 10 mg kg−1 QD group. At 6 weeks, rates were 87% vs. 69% in the 3 mg kg−1 QD group ( P = 0.009), and 75% vs. 61% in the 10 mg kg−1 QD group ( P = 0.01). Patients with possible invasive mould disease based on EORTC/MSG 2008 criteria had improved survival rates compared with those treated for probable/proven invasive mould disease. As possible invasive mould disease probably reflects an early-stage of disease, a better outcome might be expected when treatment with liposomal amphotericin B is started preemptively. [ABSTRACT FROM AUTHOR]

A 56‐year‐old patient with a history of bilateral lung transplantation for idiopathic interstitial pneumonia not responding to corticosteroids therapy had a good initial postoperative outcome. One month later, subcutaneous nodules appeared and histopathology revealed septate hyphae in the nodules and Aspergillus fumigatus in bronchial lavage. FDG PET/CT and CMR revealed multiple left and right ventricles abscesses consistent with cardiac aspergillosis. The combination of FDG PET/CT and CMR was useful to detect the cardiac localization of systemic aspergillosis, to define the precise morphological details of myocardial lesions and to evaluate the response to treatment. [ABSTRACT FROM AUTHOR]

The article discusses the results of a clinical study that was conducted to investigate the causes of death among patients who undergone treatment for invasive aspergillosis (IA). Of the total 277 patients participated, 98 died during the 12-week course of the study. It mentions that voriconazole was assigned to 144 patients while amphotericin B was recieved by the remaining 133 patients.

Background: Invasive aspergillosis (IA) has a poor prognosis in immunocompromised patients. Combinations of drugs that act on different targets are expected to improve the clinical efficacy of separate compounds.Methods: Patients with proven or probable IA were randomized in a prospective, open pilot study to receive either a combination of liposomal amphotericin B (AmB) at the standard dose (3 mg/kg daily) and caspofungin at the standard dose or monotherapy with a high-dose AmB regimen (10 mg/kg daily).Results: Thirty patients (21 men and 9 women) with hematologic malignancies were analyzed, and there were 15 patients in each arm. The median duration of treatment was 18 days for the combination group and 17 days for the high-dose monotherapy group. At the end of treatment, there were significantly more favorable overall responses (partial or complete responses; P = .028) in the combination group (10 of 15 patients; 67%) compared with the high-dose monotherapy group (4 of 15 patients; 27%). Survival rates at 12 weeks after inclusion were 100% and 80%, respectively. Infusion-related reactions occurred in 3 patients in the high-dose monotherapy group. A 2-fold increase in serum creatinine occurred in 4 of 17 patients (23%) who received high-dose monotherapy and 1 of 15 patient (7%) who received combination therapy; hypokalemia <3 mmol/L occurred in 3 patients and 2 patients, respectively.Conclusions: The combination of liposomal AmB and caspofungin was promising as therapy for IA compared with monotherapy. A trial that includes more patients will be required next to confirm the results of this pilot study. [ABSTRACT FROM AUTHOR]

Post-transplant lymphoproliferative disorders (PTLD) are severe complications after solid organ transplantation with no consensus on best treatment practice. Chemotherapy is a therapeutic option with a high response and a significant relapse rate leading to a low long-term tolerance rate. Currently, most centres use anthracycline-based drug combinations, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone). We assessed the efficacy and safety of a dose-adjusted ACVBP (doxorubicin reduced to 50 mg/m2, cyclophosphamide adjusted to renal function, vindesine, bleomycin, prednisone) regimen in patients failing to respond to a reduction in immunosuppressive therapy. Favourable responses were observed in 24 (73%) of the 33 treated patients. Fourteen (42%) patients died, mostly from PTLD progression. Actuarial survival was 60% at 5 years and 55% at 10 years. Survival prognostic factors were: number of involved sites ( P = 0·007), clinical stage III/IV ( P = 0·004), bulky tumour ( P < 0·0001), B symptoms ( P = 0·03), decreased serum albumin ( P = 0·03) and poor performance status ( P = 0·06). Both the international and the PTLD prognostic index were predictive for survival ( P = 0·001 and P = 0·002, respectively). Overall 128 cycles were given. Grade 3 or 4 neutropenia was recorded after 26 (20%) chemotherapy cycles in 19 (58%) patients. Forty-one (32%) infections were recorded in 26 (79%) patients. This study demonstrated that an individual dose-adjustment of ACVBP regimen was manageable in PTLD patients and favourably impacted on long-term survival. [ABSTRACT FROM AUTHOR]

It has been suggested that a better outcome of neutropenia-associated invasive fungal infections can be achieved when high doses of lipid formulations of amphotericin B are used. We now report a randomized multicentre study comparing liposomal amphotericin B (AmBisome, 5 mg/kg/d) to amphotericin B deoxycholate (AmB, 1 mg/kg/d) in the treatment of these infections. Of 106 possible patients, 66 were enrolled and analysed for efficacy: nine had documented fungaemia, 17 had other invasive mould infections and 40 had suspected pulmonary aspergillosis. After completion of the course medication, in the AmBisome group (n = 32) 14 patients had achieved complete response, seven a partial response and 11 were failures as compared to 6, 13 and 15 patients (n = 34) treated with AmB (P = 0.09); P = 0.03 for complete responders. A favourable trend for AmBisome was found at day 14, in patients with documented infections and in patients with pulmonary aspergillosis (P = 0.05 and P = 0.096 respectively). Mortality rates were lower in patients treated with AmBisome (adjusted for malignancy status, P = 0.03). More patients on AmB had a >100% increase of their baseline serum creatinine (P < 0.001). The results indicate that, in neutropenic patients with documented or suspected invasive fungal infections AmBisome 5 mg/kg/d was superior to AmB 1 mg/kg/d with respect to efficacy and safety. [ABSTRACT FROM AUTHOR]

AIMS To report a case of severe delayed methotrexate elimination attributable to consumption of a cola beverage. METHODS To investigate unexplained low urinary pH in a lymphoma patient treated with high-dose methotrexate. RESULTS Unexpected urinary acidity, despite administration of large amounts of sodium bicarbonate, could be attributed to repeated consumption of a cola beverage. It resulted in a delayed elimination of methotrexate and acute renal failure. Discontinuation of cola drinks, increase in calcium folinate rescue and in sodium bicarbonate allowed satisfactory elimination of methotrexate on day 12 after infusion and recovery from renal impairment without other severe toxicity. No other cause of delay in methotrexate elimination could be identified. CONCLUSIONS Cola beverages have a low pH due to their phosphoric acid content that is excreted by renal route. We recommend patients receiving high dose methotrexate abstain from any cola drink within 24 h before and during methotrexate administration and until complete elimination of the drug. [ABSTRACT FROM AUTHOR]