Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome.

Treatment results of AML in elderly patients are unsatisfactory. In an open label randomized phase II study, we investigated whether addition of the XPO1 inhibitor selinexor to intensive chemotherapy would improve outcome in this population. 102 AML patients > 65 years of age (median 69 (65-80)) were randomly assigned to standard chemotherapy (3 + 7) with or without oral selinexor 60 mg twice weekly (both arms n = 51), days 1-24. In the second cycle, cytarabine 1000 mg/m2 twice daily, days 1-6 with or without selinexor was given. CR/CRi rates were significantly higher in the control arm than in the investigational arm (80% (95% C.I. 69-91%) vs. 59% (45-72%; p = 0.018), respectively). At 18 months, event-free survival was 45% for the control arm versus 26% for the investigational arm (Cox-p = 0.012) and overall survival 58% vs. 33%, respectively (p = 0.009). AML and infectious complications accounted for an increased death rate in the investigational arm. Irrespective of treatment, MRD status after two cycles appeared to be correlated with survival. We conclude that the addition of selinexor to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients. (Netherlands Trial Registry number NL5748 (NTR5902), www.trialregister.nl ).

Correction: Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS.

More effective treatment modalities are urgently needed in patients with acute myeloid leukemia (AML) of older age. We hypothesized that adding lenalidomide to intensive standard chemotherapy might improve their outcome. After establishing a safe lenalidomide, dose elderly patients with AML were randomly assigned in this randomized Phase 2 study (n = 222) to receive standard chemotherapy ("3 + 7") with or without lenalidomide at a dose of 20 mg/day 1-21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without lenalidomide (20 mg/day 1-21). The CR/CRi rates in the two arms were not different (69 vs. 66%). Event-free survival (EFS) at 36 months was 19% for the standard arm versus 21% for the lenalidomide arm and overall survival (OS) 35% vs. 30%, respectively. The frequencies and grade of adverse events were not significantly different between the treatment arms. Cardiovascular toxicities were rare and equally distributed between the arms. The results of the present study show that the addition of lenalidomide to standard remission induction chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR2294 in The NederlandsTrial Register (www.trialregister.nl).

Voriconazole plus terbinafine combination antifungal therapy for invasive Lomentospora prolificans infections: analysis of 41 patients from the FungiScope® registry 2008-2019.

OBJECTIVES: Lomentospora prolificans is an emerging cause of serious invasive fungal infections. Optimal treatment of these infections is unknown, although voriconazole-containing treatment regimens are considered the treatment of choice. The objective of this study was to evaluate the role of combination antifungal therapy for L. prolificans infections. METHODS: We performed a retrospective review of medical records of patients with invasive L. prolificans infection diagnosed between 1 January 2008 and 9 September 2019 that were documented in the FungiScope® registry of rare invasive fungal infections. We compared clinical outcomes between antifungal treatment strategies. RESULTS: Over the study period, 41 individuals with invasive L. prolificans infection from eight different countries were documented in the FungiScope® registry. Overall, 17/40 (43%) had treatment response/stable disease and 21/40 (53%) had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was associated with increased 28-day survival (15/24 survived versus 4/16 receiving monotherapy; p 0.027) and the combination voriconazole plus terbinafine trended to be associated with higher rates of treatment success (10/16, 63%, 95% CI 35%-85%) compared with other antifungal treatment regimens (7/24, 29%, 95% CI 13%-51%, p 0.053). In Kaplan-Meier survival analysis there was a higher survival probability in individuals receiving the voriconazole/terbinafine combination compared with other antifungal regimens (median survival 150 days versus 17 days). CONCLUSIONS: While overall mortality was high, combination antifungal treatment, and in particular combination therapy with voriconazole plus terbinafine may be associated with improved treatment outcomes compared with other antifungal regimens for the treatment of invasive L. prolificans infections.

Evaluation of health and quality of life in apheresis patients - data from the WAA register.

OBJECTIVE: The World Apheresis Association (WAA) register contains data from more than 89 000 apheresis procedures in more than 12,000 patients. The aim of this study was to evaluate functional health and quality of life (QoL) in patients during apheresis treatment. MATERIAL AND METHODS: Estimates of health condition (HC) were made in 40,445 and of QoL in 22112 apheresis procedures. This study focused on a 10-step graded evaluation of HC (scale from: 'bedridden, unable to eat' to a level of 'athletic competition') and self-assessment of QoL (scale from: worst ever '0' to best ever '10'). Data were compared in relation to various apheresis procedures and if the patient underwent the first or subsequent apheresis procedure. RESULTS: Of the patients treated with plasma exchange (PEX) with centrifugation technique (n = 15787) 10% were 'bedridden, unable to come out of bed' while for patients treated with plasma filtration technique (n = 1018) the percentage was 27%. During the first procedure these figures were 16% and 30%, respectively. Self-estimates of QoL were graded 'zero' or '1' in 1.6% of patients during the first apheresis procedure; At the first contact patients undergoing PEX graded like this in 4.3%. CONCLUSION: Many of the patients undergoing apheresis treatment have poor HC and QoL at the start of therapy. Of all therapeutic apheresis procedures patients undergoing PEX had the lowest score of QoL.

Distribution of indications and procedures within the framework of centers participating in the WAA apheresis registry.

The WAA apheresis registry was established in 2003 and an increasing number of centers have since then included their experience and data of their procedures. The registry now contains data of more than 74,000 apheresis procedures in more than 10,000 patients. This report shows that the indications for apheresis procedures are changing towards more oncological diagnoses and stem cell collections from patients and donors and less therapeutic apheresis procedures. In centers that continue to register, the total extent of apheresis procedures and patients treated have expanded during the latest years.

Adverse events in apheresis: An update of the WAA registry data.

Apheresis with different procedures and devices are used for a variety of indications that may have different adverse events (AEs). The aim of this study was to clarify the extent and possible reasons of various side effects based on data from a multinational registry. The WAA-apheresis registry data focus on adverse events in a total of 50846 procedures in 7142 patients (42% women). AEs were graded as mild, moderate (need for medication), severe (interruption due to the AE) or death (due to AE). More AEs occurred during the first procedures versus subsequent (8.4 and 5.5%, respectively). AEs were mild in 2.4% (due to access 54%, device 7%, hypotension 15%, tingling 8%), moderate in 3% (tingling 58%, urticaria 15%, hypotension 10%, nausea 3%), and severe in 0.4% of procedures (syncope/hypotension 32%, urticaria 17%, chills/fever 8%, arrhythmia/asystole 4.5%, nausea/vomiting 4%). Hypotension was most common if albumin was used as the replacement fluid, and urticaria when plasma was used. Arrhythmia occurred to similar extents when using plasma or albumin as replacement. In 64% of procedures with bronchospasm, plasma was part of the replacement fluid used. Severe AEs are rare. Although most reactions are mild and moderate, several side effects may be critical for the patient. We present side effects in relation to the procedures and suggest that safety is increased by regular vital sign measurements, cardiac monitoring and by having emergency equipment nearby.

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey.

OBJECTIVES: We evaluated azacitidine (Vidaza(®)) safety and efficacy in patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), in a real-life setting. Treatment response, dose, and schedule were assessed. METHODS: This non-interventional, post-marketing survey included 49/50 patients receiving azacitidine at 14 Belgian haematology centres from 2010-2012. Treatment-emergent adverse events (TEAEs), including treatment-related TEAEs, and serious TEAEs (TESAEs) were recorded throughout the study. Treatment response [complete response (CR), partial response (PR), haematological improvement (HI), stable disease (SD), treatment failure (TF)) and transfusion-independence (TI) were evaluated at completion of a 1-year observation period (1YOP) or at treatment discontinuation, and overall survival (OS), at study conclusion. RESULTS: The median age of patients was 74·7 (range: 43·9-87·8) years; 69·4% had MDS, 26·5% had primary or secondary AML, and 4·1% had CMML. Treatment-related TEAEs, grade 3-4 TEAEs, and TESAEs were reported in 67·3%, 28·6%, and 18·4% of patients, respectively. During 1YOP, patients received a median of 7 (1-12) treatment cycles. Treatment response was assessed for 38/49 patients. Among MDS and CMML patients (n = 29), 41·4% had CR, PR, or HI, 41·4% had SD, and 17·2% had TF. Among AML patients (n = 9), 44·4% had CR or PR, 33·3% had SD, and 22·2% had TF. TI was observed in 14/32 (43·8%) patients who were transfusion-dependent at baseline. Median (95% confidence interval) OS was 490 (326-555) days; 1-year OS estimate was 0·571 (0·422-0·696). CONCLUSIONS: Our data support previous findings that azacitidine has a clinically acceptable safety profile and shows efficacy.

Relapsing infiltrates after pneumocystis pneumonia in stem cell transplant patients: think about BOOP!

Bronchiolitis Obliterans Organizing Pneumonia (BOOP) can complicate allogeneic haematopoietic stem cell transplantation. It is associated with prior graft-versus-host disease (GVHD) and the case fatality is 21%. In 22%, diagnosis is preceded by tapering the corticosteroids given as a treatment for GVHD. We report a fatal case of BOOP after tapering the corticosteroids that the patient received for a Pneumocystis jirovecii pneumonia after stem cell transplantation.

Cancer presenting as fatal pulmonary tumour embolism.

Rapidly fatal pulmonary tumour embolism is a rare complication of malignancy, and often presents as progressive dyspnea without obvious cause. We describe two cases presenting with a dramatic clinical picture of lactic acidosis and cardiopulmonary arrest soon after admission on ICU. The first patient was a 29-year old woman with a breast cancer seeming in remission who was admitted with rapidly increasing dyspnea since two weeks. The second patient was a 46-year old woman with HIV and no history of malignancy, who developed dyspnea and lactic acidosis over the course of a few days while she was investigated for an occipital brain lesion. Both patients died soon after admission and massive tumour emboli were found on autopsy. Breast cancer was the origin of the emboli in both cases. Symptoms were out of proportion to the initial physical cardiopulmonary findings and radiographic features. Clinical signs of pulmonary tumour embolism are non-specific and subacute. Prognosis is poor and definite diagnosis is usually made post-mortem. Solid malignancies such as breast cancer account for most of the cases. Pulmonary tumour embolism should be considered in critically ill patients with unexplained hypoxemia and lactic acidosis, mild or no radiological abnormalities and fast clinical deterioration. It may occur in young patients and in patients without history of malignancy.

Tuberculosis of the spine: CT and MR imaging features.

Tuberculosis (TB) remains endemic in most of the developing countries. However, a resurgence of tuberculosis has also been reported in the past decades in developed countries, not only in the lungs, but also in extrapulmonary sites, e.g. the vertebral column. Vertebral TB is most often found in the lower thoracic and upper lumbar regions. Diagnosis is often difficult; clinical findings are usually non-specific and radiologic features may mimic those of other bacterial, fungal, inflammatory and neoplastic diseases. However, recognition and understanding of the radiological findings may help in diagnosis. Two distinct patterns of vertebral tuberculosis may be seen: the classic finding of spondylodiscitis, characterized by destruction of two or more contiguous vertebrae and opposed end plates, disk infection, and commonly a paraspinal mass or collection. The second pattern, increasing in frequency, is a atypical form of spondylitis without disk involvement.The value of CT and MR imaging are discussed in the diagnostic workup of vertebral tuberculosis. A positive culture or histopathologic analysis of CT-guided needle aspiration or biopsy specimens is required in the absence of pulmonary manifestations of tuberculosis for definitive diagnosis and adequate treatment.

Abdominal tuberculous lymphadenopathy: MRI features.

The aim of this study was to describe the MRI features of abdominal tuberculous lymphadenopathy. MRI studies of 13 patients with abdominal tuberculous lymphadenopathy were reviewed with regard to anatomic distribution and size. Signal intensities, in relation to abdominal wall muscle, on unenhanced T1- and T2-weighted images and patterns of contrast enhancement of lymphadenopathy were evaluated in each patient. In each patient, the largest lymph node with the same imaging characteristic was evaluated. The upper paraaortic region was the most common site of involvement (n=12 patients), followed by the lesser omentum (n=10 patients), the anterior pararenal space (n=9 patients), the lower paraaortic area (n=8 patients), the small bowel mesentery (n=6 patients), the greater omentum (n=2 patients) and the originating site of the inferior mesenteric artery (n=2 patients). The mean lymph node size was 1.8 cm (range 0.5-5 cm). The overall mean lymph node number per patient was 16 (range 2-50). A total of 41 lymph nodes were evaluated in 13 patients. On T2-weighted images, 40 lesions were hyperintense and one lesion was isointense. Nine hyperintense lesions showed a hypointense peripheral rim and seven internal heterogeneïty. Perinodal T2-hyperintensity was present in 23 lesions. The latter finding was valid for all patients. On T1-weighted images, 30 lesions were hypointense and 11 isointense. Nine hypointense lesions demonstrated a hyperintense peripheral rim, and six were heterogeneous. Contrast-enhanced fat-suppressed T1-weighted images demonstrated predominant peripheral enhancement in 28 lesions: (1) peripheral uniform, thin (n=19); (2) thick irregular, complete (n=3); and (3) conglomerate group of nodes showing peripheral and central areas of rim enhancement (n=6). Heterogeneous and homogeneous enhancement was present in ten and three lesions, respectively. Combinations of enhancing patterns in the same nodal group and different nodal groups were seen in eight and nine patients, respectively. Abdominal tuberculous lymphadenopathy may show a variety of signal intensities and patterns of contrast enhancement on MRI. Lymphadenopathy, hypointense on T1-weighted, hyperintense on T2-weighted images with perinodal hyperintensity, and predominant peripheral rimlike enhancement may suggest the diagnosis of tuberculosis.

Treatment of hepatitis B virus-related polyarteritis nodosa: two case reports and a review of the literature.

A substantial number of cases of polyarteritis nodosa (PAN) are related to hepatitis B virus (HBV) infection. Different treatment strategies are reported in the literature. The aim of this study was to review 15 years of literature (1988-2002) to determine the optimal treatment for HBV-related PAN at present, and to discuss the indications and mechanism of action of corticosteroids in HBV-related PAN, as many physicians are reluctant to use these in the presence of HBV infection. The first patient stopped his initial treatment, relapsed and died of cerebral infarction. The second case illustrates the favorable outcome with the standard treatment: corticosteroids, lamivudine and plasma exchanges. If adequate follow-up is possible, antiviral agents as well as corticosteroids are indicated in HBV-related PAN. Corticosteroids diminish inflammation and corticosteroid withdrawal induces an alanine aminotransferase (ALT) rebound in patients with a low baseline ALT level. Antiviral agents are essential, as they reduce the production of HBV antigens and help to achieve hepatitis B early antigen (HBeAg) seroconversion. Plasma exchanges reduce the level of circulating immune complexes and are included in the treatment protocol of all recent studies. However, their effect has not been evaluated in controlled trials. We concluded that if adequate follow-up is possible, antiviral agents as well as corticosteroids are indicated in HBV-related PAN.

[Weight loss, joint pain and abdominal lymphadenopathy as signs of sarcoidosis, but also of Whipple's disease]. / Gewichtsverlies, pijnlijke gewrichten en vergrote klieren in de buik als uitingen van sarcoïdose, maar ook van de ziekte van Whipple.

Two patients, a woman aged 66 and a man aged 56 years, with an inflammatory syndrome, weight loss, joint pain and abdominal lymphadenopathy received long-term treatment with corticosteroids for alleged sarcoidosis. No long-term remission was induced and the patients were referred for a second opinion. Eventually the diagnosis of Whipple's disease was established 5 years after the appearance of the first symptoms in the case of the female patient and 4 years after in the case of the male patient. Both patients showed a marked clinical improvement after treatment with trimethoprim-sulfamethoxazole. An atypical presentation of alleged sarcoidosis should suggest the possibility of Whipple's disease, especially in the case of gastrointestinal symptoms and the failure to respond to corticosteroids, and warrants duodenal biopsy. The presence of granulomas with an elevated angiotensin-converting enzyme level is not pathognomonic for sarcoidosis. It is vitally important to distinguish the two disorders, as Whipple's disease is an infectious disorder that requires antibiotic therapy to prevent a fatal outcome.