Transfusion of ever-pregnant donor red blood cells and mortality of male patients.

Previous studies found exposure to red blood cell transfusions from female donors who have been pregnant reduces survival in male patients compared to exposure to male donor products, but evidence is not consistent. We postulate the previously observed association is modified by offspring sex, with an expected increased mortality risk for male patients receiving units from female donors with sons. Here, marginal structural models were used to assess the association between exposure to units from ever-pregnant donors, ever-pregnant donors with sons and ever-pregnant donors with daughters, and mortality. Clinical data were collected on first-ever transfusion recipients in the Netherlands and donor data were supplemented with information about offspring sex and date of birth. In this analysis, 56,825 patients were included, of whom 8,288 died during follow-up. Exposure to red blood cell units from everpregnant donors with sons was not associated with increased all-cause mortality risk among male transfusion recipients (hazard ratio [HR] 0.91, 95% confidence interval 0.83-1.01). Exposure to ever-pregnant donors, irrespective of offspring sex, was associated with mortality in male patients aged between 18 and 50 years (ever-pregnant donors: HR 1.81, 95% CI 1.31-2.51) compared to male donor units, but was protective in female patients. This study suggests that the observed increased mortality risk for exposure to red blood cell units from parous female donors does not depend on offspring sex. The increased risk of mortality seen in younger adult male patients is consistent with previous observations, but the underlying biological mechanism could not be identified in this study.

Donor pregnancies and transfusion recipient mortality: A role for red blood cell storage?

BACKGROUND AND OBJECTIVES: Donor characteristics have been implicated in transfusion-related adverse events. Uncertainty remains about whether sex, and specifically pregnancy history of the blood donor, could affect patient outcomes. Whether storage duration of the blood product could be important for patient outcomes has also been investigated, and a small detrimental effect of fresh products remains a possibility. Here, we hypothesize that fresh red blood cell products donated by ever-pregnant donors are associated with mortality in male patients. MATERIALS AND METHODS: We used data from a cohort study of adult patients receiving a first transfusion between 2005 and 2015 in the Netherlands. The risk of death after receiving a transfusion from one of five exposure categories (female never-pregnant stored ≤10 days, female never-pregnant stored >10 days, female ever-pregnant stored ≤10 days, female ever-pregnant stored >10 days and male stored for ≤10 days), compared to receiving a unit donated by a male donor, which was stored for >10 days (reference), was calculated using a Cox proportional hazards model. RESULTS: The study included 42,456 patients who contributed 88,538 person-years in total, of whom 13,948 died during the follow-up of the study (33%). Fresh units (stored for ≤10 days) from ever-pregnant donors were associated with mortality in male patients, but the association was not statistically significant (hazard ratio 1.39, 95% confidence interval 0.97-1.99). Sensitivity analyses did not corroborate this finding. CONCLUSION: These findings do not consistently support the notion that the observed association between ever-pregnant donor units and mortality is mediated by blood product storage.

Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naive myelofibrosis.

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm, typically associated with disease-related symptoms, splenomegaly, cytopenias and bone marrow fibrosis. Patients experience a significant symptom burden and a reduced life expectancy. Patients with MF receive ruxolitinib as the current standard of care, but the depth and durability of responses and the percentage of patients achieving clinical outcome measures are limited; thus, a significant unmet medical need exists. Pelabresib is an investigational small-molecule bromodomain and extraterminal domain inhibitor currently in clinical development for MF. The aim of this article is to describe the design of the ongoing, global, phase III, double-blind, placebo-controlled MANIFEST-2 study evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with JAKi treatment-naive MF. Clinical Trial Registration: NCT04603495 (ClinicalTrials.gov).

Myelofibrosis (MF) is a rare type of blood cancer that interferes with the process of blood cell production by the bone marrow. In patients with MF, the bone marrow becomes overactive, leading to scarring and subsequently a lack of healthy blood cells being produced. The main symptoms of MF include anemia, fatigue, weakness and pain or discomfort in the abdomen. MF is associated with a shortened life expectancy. The current go-to treatment for MF is ruxolitinib. However, ruxolitinib has shown limited efficacy in improving clinical symptoms long term; so, new safe and effective treatments are needed. Pelabresib is a novel drug currently in clinical development for treating MF. The aim of this article is to describe the design of the ongoing, global phase III MANIFEST-2 study. MANIFEST-2 is evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with MF.

Autologous transplantation for transformed non-Hodgkin lymphoma using an yttrium-90 ibritumomab tiuxetan conditioning regimen.

Transformation from indolent non-Hodgkin lymphoma (NHL) to diffuse large B cell lymphoma (DLBCL) has historically been associated with a poor prognosis. A small series of autologous stem cell transplantation (ASCT) studies using conventional conditioning regimens has demonstrated durable progression-free survival (PFS) rates ranging from 25% to 47%, but data in the rituximab era are lacking. Here we report the results of a multicenter retrospective trial evaluating ASCT in patients with transformed lymphoma using the Z-BEAM conditioning regimen, which combines yttrium-90-labeled ibritumomab tiuxetan (Zevalin) with high-dose BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy. Sixty-three patients from 4 institutions were treated between 2003 and 2011. Histological confirmation of transformation was required and defined as a diagnosis of DLBCL in patients with either a prior history or concomitant diagnosis of low-grade B cell NHL. Median patient age at ASCT was 59.5 years, median number of prior regimens was 2, and all patients were exposed to rituximab. Disease status at ASCT was as follows: first complete remission (CR) (n = 30), first partial remission (n = 11), first relapse (n = 14), and at least second CR (n = 8). The median time from diagnosis of histological transformation to ASCT was 7.5 months (range, 2.8 to 116). Two-year nonrelapse mortality was 0%. Median follow-up for living patients was 28 months (range, 5 to 103). Two-year PFS was 68% (95% confidence interval, 58% to 75%), and overall survival was 90% (95% confidence interval, 80% to 95%). In conclusion, the Z-BEAM conditioning regimen for ASCT is well tolerated by patients with transformed lymphoma and demonstrates encouraging clinical outcomes.

An Acute Promyelocytic Leukemia Resistant to All-Trans Retinoic Acid: A Case Report of the ZBTB16::RARa Variant and Review of the Literature.

Introduction: Acute promyelocytic leukemia (APL) is characterized by the PML::RARa gene fusion and treatment consists of all-trans retinoic acid (ATRA). Rarely, genetic APL variants have been described which are insensitive to ATRA treatment and are therefore associated with a worse prognosis. Rapid identification of the APL variant is essential to start the correct treatment. Case Presentation: Here, we present a case of a 66-year-old male patient with weight loss and arthralgia. Laboratory results showed an anemia and mild leukocytosis with predominantly monocytes. Bone marrow investigation unexpectedly revealed a t(11;17)(q23;q21). This raised suspicion of an ATRA-resistant APL. By demonstrating the ZBTB16::RARa gene fusion, the diagnosis was confirmed. Conclusion: This case study emphasizes the importance of integrated diagnostics and provides guidance to recognize the ZBTB16::RARa APL, which is the most prevalent ATRA-resistant APL. Furthermore, an overview of other genetic APL variants is presented and how to treat these uncommon diseases in clinical practice.

Characterizing the Bone Marrow Environment in Advanced-Stage Myelofibrosis during Ruxolitinib Treatment Using PET/CT and MRI: A Pilot Study.

Current diagnostic criteria for myelofibrosis are largely based on bone marrow (BM) biopsy results. However, these have several limitations, including sampling errors. Explorative studies have indicated that imaging might form an alternative for the evaluation of disease activity, but the heterogeneity in BM abnormalities complicates the choice for the optimal technique. In our prospective diagnostic pilot study, we aimed to visualize all BM abnormalities in myelofibrosis before and during ruxolitinib treatment using both PET/CT and MRI. A random sample of patients was scheduled for examinations at baseline and after 6 and 18 months of treatment, including clinical and laboratory examinations, BM biopsies, MRI (T1-weighted, Dixon, dynamic contrast-enhanced (DCE)) and PET/CT ([15O]water, [18F]NaF)). At baseline, all patients showed low BM fat content (indicated by T1-weighted MRI and Dixon), increased BM blood flow (as measured by [15O]water PET/CT), and increased osteoblastic activity (reflected by increased skeletal [18F]NaF uptake). One patient died after the baseline evaluation. In the others, BM fat content increased to various degrees during treatment. Normalization of BM blood flow (as reflected by [15O]water PET/CT and DCE-MRI) occurred in one patient, who also showed the fastest clinical response. Vertebral [18F]NaF uptake remained stable in all patients. In evaluable cases, histopathological parameters were not accurately reflected by imaging results. A case of sampling error was suspected. We conclude that imaging results can provide information on functional processes and disease distribution throughout the BM. Differences in early treatment responses were especially reflected by T1-weighted MRI. Limitations in the gold standard hampered the evaluation of diagnostic accuracy.

Therapeutic drug monitoring-guided treatment versus standard dosing of voriconazole for invasive aspergillosis in haematological patients: a multicentre, prospective, cluster randomised, crossover clinical trial.

OBJECTIVES: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treatment is superior to standard treatment for invasive aspergillosis. METHODS: A multicentre (n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged ≥18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treatment initiation of voriconazole and repeated during treatment in both groups. The TDM group had measured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. RESULTS: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups (P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) (P < 0.001). CONCLUSIONS: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov registration no. NCT00893555.

MANIFEST: Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Myelofibrosis.

PURPOSE: Standard therapy for myelofibrosis comprises Janus kinase inhibitors (JAKis), yet spleen response rates of 30%-40%, high discontinuation rates, and a lack of disease modification highlight an unmet need. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). METHODS: MANIFEST (ClinicalTrails.gov identifier: NCT02158858), a global, open-label, nonrandomized, multicohort, phase II study, includes a cohort of JAKi-naïve patients with myelofibrosis treated with pelabresib and ruxolitinib. The primary end point is a spleen volume reduction of ≥ 35% (SVR35) at 24 weeks. RESULTS: Eighty-four patients received ≥ 1 dose of pelabresib and ruxolitinib. The median age was 68 (range, 37-85) years; 24% of patients were intermediate-1 risk, 61% were intermediate-2 risk, and 16% were high risk as per the Dynamic International Prognostic Scoring System; 66% (55 of 84) of patients had a hemoglobin level of < 10 g/dL at baseline. At 24 weeks, 68% (57 of 84) achieved SVR35, and 56% (46 of 82) achieved a total symptom score reduction of ≥ 50% (TSS50). Additional benefits at week 24 included 36% (29 of 84) of patients with improved hemoglobin levels (mean, 1.3 g/dL; median, 0.8 g/dL), 28% (16 of 57) with ≥ 1 grade improvement in fibrosis, and 29.5% (13 of 44) with > 25% reduction in JAK2V617F-mutant allele fraction, which was associated with SVR35 response (P = .018, Fisher's exact test). At 48 weeks, 60% (47 of 79) of patients had SVR35 response. Grade 3 or 4 toxicities seen in ≥ 10% patients were thrombocytopenia (12%) and anemia (35%), leading to treatment discontinuation in three patients. 95% (80 of 84) of the study participants continued combination therapy beyond 24 weeks. CONCLUSION: The rational combination of the BETi pelabresib and ruxolitinib in JAKi-naïve patients with myelofibrosis was well tolerated and showed durable improvements in spleen and symptom burden, with associated biomarker findings of potential disease-modifying activity.

A population-based study on different regimens of R-CHOP in patients with newly diagnosed DLBCL in The Netherlands.

Randomized controlled trials have studied different dose-intensity and dose-interval regimens of R-CHOP for patients with diffuse large B-cell lymphoma (DLBCL). This study was undertaken to confirm these results in a population-based setting, with special emphasis on the value of 6xR-CHOP21 among patients aged 18-64 years. Two thousand three hundred and thirty-eight stage II-IV DLBCL patients, ≥18 years, we confirmed the similar efficacy of six versus eight cycles of R-CHOP and of R-CHOP21 versus R-CHOP14 regimens across all age groups on overall survival (median follow-up 36.4 (1.3-167.6) months). Nevertheless, overall survival decreased with older age. Interestingly, in patients 18-64 years, the adjusted risk of mortality among recipients of 6xR-CHOP21 compared to other R-CHOP regimens seems to be similar (HR 0.62; 95%CI: 0.38-1.02; p= .059). Although this finding might suggest that 6xR-CHOP21 could be considered as first-line regimen for all stage II-IV DLBCL patients, it should be confirmed in forthcoming population-based studies with larger patient numbers and longitudinal follow-up.

Primary refractory follicular lymphoma: a poor outcome entity with high risk of transformation to aggressive B cell lymphoma.

BACKGROUND: Primary refractory (PREF) follicular lymphoma (FL) has a completely different clinical course from that of FL that responds to front-line treatments. In addition to having poor responses to salvage therapies, it seems that patients with PREF are at increased risk of histological transformation (HT). The Aristotle consortium presented the opportunity of investigating the risk of HT in a very large series of cases. Thus, we investigated the risk of HT in patients with PREF FL compared with that of responding patients or in stable disease and ultimately their outcome. METHODS: Six thousand three hundred thirty-nine patients from the Aristotle database were included in the analysis. These patients had a histologically confirmed grade 1, 2 or 3a FL diagnosed between 1997 and 2013. The primary end-points were the cumulative incidence (CI) of HT at the first progression or relapse and the survival after transformation. FINDINGS: The 5-year CI of HT among patients with PREF was 34% (95% confidence interval (CI): 27-43), whilst it was 7.1% (95% CI: 6.0-8.5) in the group of patients with partial response (PR) or stable disease (SD) (PR + SD) and 3.5% (95% CI: 3.0-4.2) in the group of patients achieving complete response (CR). The 5-year survival after relapse (SAR) was 33% (95% CI: 28-39) for the PREF group, 57% (95% CI 54-61) in patients with PR, 51% (95% CI 43-58) in the SD group after first-line therapy and 63% (95% CI: 66-72) in patients with CR after initial treatment (p-value <0.001). The 5-year SAR for those patients with PREF who developed HT was 21% (95% CI: 12-31), clearly diminished when compared with those patients with PREF who did not experience HT (38% [95% CI: 31-44]) (p-value = 0.001). INTERPRETATION: Patients with PREF FL have a dismal outcome and an associated very high rate of HT that further worsens their poor prognosis.

Development and testing of a tailored online fertility preservation decision aid for female cancer patients.

BACKGROUND: Decision making regarding future fertility can be very difficult for female cancer patients. To support patients in decision making, fertility preservation decision aids (DAs) are being developed. However, to make a well-informed decision, patients need personalized information tailored to their cancer type and treatment. Tailored cancer-specific DAs are not available yet. METHODS: Our DA was systematically developed by a multidisciplinary steering group (n = 21) in an iterative process of draft development, three rounds of alpha testing, and revisions. The drafts were based on current guidelines, literature, and patients' and professionals' needs. RESULTS: In total, 24 cancer-specific DAs were developed. In alpha testing, cancer survivors and professionals considered the DA very helpful in decision making, and scored an 8.5 (scale 1-10). In particular, the cancer-specific information and the tool for recognizing personal values were of great value. Revisions were made to increase readability, personalization, usability, and be more careful in giving any false hope. CONCLUSIONS: A fertility preservation DA containing cancer-specific information is important in the daily care of female cancer patients and should be broadly available. Our final Dutch version is highly appraised, valid, and usable in decision making. After evaluating its effectiveness with newly diagnosed patients, the DA can be translated and adjusted according to (inter)national guidelines.

Severe Secondary Polycythemia in a Female-to-Male Transgender Patient While Using Lifelong Hormonal Therapy: A Patient's Perspective.

After a registered drug is available on the market and used in everyday circumstances, hitherto unknown adverse drug reactions (ADRs) may occur. Furthermore, the patient can experience a previously unknown course of a known ADR. Voluntary reports by patients play an important role in gaining knowledge about ADRs in daily practice. The Netherlands Pharmacovigilance Centre Lareb received a report from a 55-year-old female-to-male transgender patient who experiences secondary polycythemia while using lifelong testosterone therapy. The onset age of the symptoms was 38 years. The symptoms appeared gradually and after approximately 1 year it was clear that the patient's hemoglobin and hematocrit had started to increase. A Naranjo assessment score of 6 was obtained, indicating a probable relationship between the patient's polycythemia and use of the suspect drug. Polycythemia is a known ADR in testosterone treatment, but little attention has been paid to the possible severity and complications of these symptoms as well as the impact on the patient's well-being.

Baseline and longitudinal variability of normal tissue uptake values of [18F]-fluorothymidine-PET images.

PURPOSE: [18F]-fluorothymidine ([18F]-FLT) is a PET-tracer enabling in-vivo visualization and quantification of tumor cell proliferation. For qualitative and quantitative analysis, adequate knowledge of normal tissue uptake is indispensable. This study aimed to quantitatively investigate baseline tracer uptake of blood pool, lung, liver and bone marrow and their precision, and to assess the longitudinal effect of systemic treatment on biodistribution. METHODS: 18F-FLT-PET(/CT) scans (dynamic or static) of 90 treatment-naïve oncological patients were retrospectively evaluated. Twenty-three patients received double baseline scans, and another 39 patients were also scanned early and late during systemic treatment with a tyrosine kinase inhibitor. Reproducible volume of interest were placed in blood pool, lung, liver, and bone marrow. For semi-quantitative analysis, SUVmean, SUVmax, and SUVpeak with several normalizations were derived. RESULTS: SUVs of basal lung, liver, and bone marrow were not significantly different between averaged dynamic and static images, in contrast with blood pool and apical lung. Highest repeatability was seen for liver and bone marrow, with repeatability coefficients of 18.6% and 20.4% when using SUVpeak. Systemic treatment with TKIs both increased and decreased normal tissue tracer uptake at early and late time points during treatment. CONCLUSION: Simultaneous evaluation of liver and bone marrow uptake in longitudinal response studies may be used to assess image quality, where changes in uptake outside repeatability limits should trigger investigators to perform additional quality control on individual PET images. ADVANCES IN KNOWLEDGE: For [18F]-FLT PET images, liver and bone marrow have low intra-patient variability when quantified with SUVpeak, but may be affected by systemic treatment. IMPLICATIONS FOR PATIENT CARE: In [18F]-FLT-PET response monitoring trials, liver and bone marrow uptake may be used for quality control of [18F]-FLT PET images.

Multiparameter flow cytometry is instrumental to distinguish myelodysplastic syndromes from non-neoplastic cytopenias.

Mandatory for the diagnosis of myelodysplastic syndromes (MDS) is the presence of dysplasia in >10% of cells within one or more cell lineages or presence of >15% ring sideroblasts or presence of MDS-associated cytogenetic (CG) abnormalities. Discrimination between neo-plastic and non-neoplastic causes of cytopenias can be challenging when dysplastic features by cytomorphology (CM) are minimal and CG abnormalities are absent or non-discriminating from other myeloid neoplastic disorders. This study evaluated a standard diagnostic approach in 379 patients with unexplained cytopenias and highlights the additional value of flow cytometry (FC) in patients with indeterminate CM and CG. CM reached no clear-cut diagnosis in 44% of the patients. Here, CG was able to identify two additional patients with MDS; other CG results did not reveal abnormalities or were not contributory. Based on the FC results, patients without a diagnosis by CM and CG were categorized 'no MDS-related features' (65%), 'limited number of MDS-related changes' (24%), and 'consistent with MDS' (11%). Patients were followed over time in an attempt to establish or confirm a diagnosis (median follow-up 391 d, range 20-1764). The specificity (true negative) of MDS-FC analysis calculated after follow-up was 95%. FC can aid as a valuable tool to exclude MDS when CM and additional CG are not conclusive in patients with cytopenia.

18F-FDG or 3'-deoxy-3'-18F-fluorothymidine to detect transformation of follicular lymphoma.

UNLABELLED: Considering the different treatment strategy for transformed follicular lymphoma (TF) as opposed to follicular lymphoma (FL), diagnosing transformation early in the disease course is important. There is evidence that (18)F-FDG has utility as a biomarker of transformation. However, quantitative thresholds may require inclusion of homogeneous non-Hodgkin lymphoma subtypes to account for differences in tracer uptake per subtype. Moreover, because proliferation is a hallmark of transformation, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) might be superior to (18)F-FDG in this setting. To define the best tracer for detection of TF, we performed a prospective a head-to-head comparison of (18)F-FDG and (18)F-FLT in patients with FL and TF. METHODS: (18)F-FDG and (18)F-FLT PET scans were obtained in 17 patients with FL and 9 patients with TF. We measured the highest maximum standardized uptake value (SUVmax), defined as the lymph node with the highest uptake per patient, and SUVrange, defined as the difference between the SUVmax of the lymph node with the highest and lowest uptake per patient. To reduce partial-volume effects, only lymph nodes larger than 3 cm(3) (A50 isocontour) were analyzed. Scans were acquired 1 h after injection of 185 MBq of (18)F-FDG or (18)F-FLT. To determine the discriminative ability of SUVmax and SUVrange of both tracers for TF, receiver-operating-characteristic curve analysis was performed. RESULTS: The highest SUVmax was significantly higher for TF than FL for both (18)F-FDG and (18)F-FLT (P < 0.001). SUVrange was significantly higher for TF than FL for (18)F-FDG (P = 0.029) but not for (18)F-FLT (P = 0.075). The ability of (18)F-FDG to discriminate between FL and TF was superior to that of (18)F-FLT for both the highest SUVmax (P = 0.039) and the SUVrange (P = 0.012). The cutoff value for the highest SUVmax of (18)F-FDG aiming at 100% sensitivity with a maximum specificity was found to be 14.5 (corresponding specificity, 82%). For (18)F-FLT, these values were 5.1 and 18%, respectively. When the same method was applied to SUVrange, the cutoff values were 5.8 for (18)F-FDG (specificity, 71%) and 1.5 for (18)F-FLT (specificity, 36%). CONCLUSION: Our data suggest that (18)F-FDG PET is a better biomarker for TF than (18)F-FLT PET. The proposed thresholds of highest SUVmax and SUVrange should be prospectively validated.

[A woman with shortness of breath and butterfly shaped cell nuclei]. / Een benauwde vrouw met vlinderkernen in het bloed.

A 53-year-old woman with respiratory discomfort came to the Emergency Department. The blood smear, made because of a new thrombocytopenia, showed leukocytes with butterfly-shaped nuclei and fine cytoplasmic granulation. The diagnosis 'microgranular variant of acute promyelocytic leukemia' was made.