Anita W. Rijneveld

Intensified chemotherapy inspired by a pediatric regimen combined with allogeneic transplantation in adult patients with acute lymphoblastic leukemia up to the age of 40

Event-free survival (EFS) at 5 years in pediatric acute lymphoblastic leukemia (ALL) is >80%. Outcome in adult ALL is still unsatisfactory, which is due to less cumulative dosing of chemotherapy and less strict adherence to timing of successive cycles. In the present phase II trial, we evaluated a pediatric regimen in adult patients with ALL under the age of 40. Treatment was according to the pediatric FRALLE approach for high-risk ALL patients and characterized by increased dosages of asparaginase, steroids, methotrexate and vincristin. However, allogeneic stem cell transplantation was offered to standard risk patients with a sibling donor and to all high-risk patients in contrast to the pediatric protocol. Feasibility was defined by achieving complete remission (CR) and completion of treatment within a strict timeframe in at least 60% of patients. In all, 54 patients were included with a median age of 26. CR was achieved in 49 patients (91%), of whom 33 completed treatment as scheduled (61%). Side effects primarily consisted of infections and occurred in 40% of patients. With a median follow-up of 32 months, EFS estimated 66% at 24 months and overall survival 72%. These data show that a dose-intensive pediatric regimen is feasible in adult ALL patients up to the age of 40.

Expression profiling of adult acute lymphoblastic leukemia identifies a BCR-ABL1-like subgroup characterized by high non-response and relapse rates

Outcome in adult precursor B-cell acute lymphoblastic leukemia (BCP-ALL) is unsatisfactory, with complete response rates of approximately 80% and event-free survival at 5 years of only 40%–50%.[1][1] This inferior survival in adult compared with pediatric patients might be explained by a higher

Circulating endothelial cells: a potential parameter of organ damage in sickle cell anemia?

Objective laboratory tools are needed to monitor developing organ damage in sickle cell disease (SCD). Circulating endothelial cells (CECs) are indicative of vascular injury. We determined whether elevated CEC can be detected in asymptomatic SCD with the CellSearch system and whether the CEC count is related to clinical and blood-based biomarkers of disease severity. Fifteen consecutive clinically asymptomatic HbSS patients and 15 matched HbAA controls were analyzed for CEC counts, laboratory parameters of disease severity (Hb, leukocyte counts, HbF%), plasma levels of markers for endothelial activation (sVCAM-1, VWF:Ag) and of endogenous inhibitors of nitric oxide synthase (asymmetrical dimethylarginine [ADMA]). CEC counts were significantly higher in patients (12 cells/mL, IQR 8-29) as compared to controls (4 cells/mL, 3-10) (P=0.007). CEC counts were significantly higher in patients with pulmonary hypertension (PHT) (P=0.015), and increased with increasing number of affected organs (0-4 involved organs, P=0.002). No significant correlations between CEC and any other laboratory parameter were detected. In conclusion, CECs could prove to be an important new tool for assessing developing vasculopathy and organ damage in SCD.

Early occurrence of red blood cell alloimmunization in patients with sickle cell disease

Red blood cell (RBC) alloimmunization is a major complication of transfusion therapy in sickle cell disease (SCD). Identification of high‐risk patients is hampered by lack of studies that take the cumulative transfusion exposure into account. In this retrospective cohort study among previously non‐transfused SCD patients in the Netherlands, we aimed to elucidate the association between the cumulative transfusion exposure, first alloimmunization and independent risk factors. A total of 245 patients received 11u2009952 RBC units. Alloimmunization occurred in 43 patients (18%), half of them formed their first alloantibody before the 8th unit. In patients with exposure to non‐extended matched transfusions (ABO and RhD) the cumulative alloimmunization risk increased up to 35% after 60 transfused units. This was significantly higher compared to a general transfused population (HR 6.6, CI 4.2–10.6). Receiving the first transfusion after the age of 5 was an independent risk factor for alloimmunization (HR 2.3, CI 1.0–5.1). Incidental, episodic transfusions in comparison to chronic scheme transfusions (HR 2.3, CI 0.9–6.0), and exposure to non‐extended matched units in comparison to extended matching (HR 2.0, CI 0.9–4.6) seemed to confer a higher alloimmunization risk. The majority of first alloantibodies are formed after minor transfusion exposure, substantiating suggestions of a responder phenotype in SCD and stressing the need for risk factor identification. In this study, older age at first transfusion, episodic transfusions and non‐extended matched transfusions appeared to be risk factors for alloimmunization. Am. J. Hematol. 91:763–769, 2016.

Intensive chemotherapy to improve outcome in patients with acute lymphoblastic leukemia over the age of 40: a phase II study for efficacy and feasibility by HOVON

Intensive chemotherapy to improve outcome in patients with acute lymphoblastic leukemia over the age of 40: a phase II study for efficacy and feasibility by HOVON

Nonclassical FCGR2C haplotype is associated with protection from red blood cell alloimmunization in sickle cell disease

Red blood cell (RBC) transfusions are of vital importance in patients with sickle cell disease (SCD). However, a major complication of transfusion therapy is alloimmunization. The low-affinity Fcγ receptors, expressed on immune cells, are important regulators of antibody responses. Genetic variation in FCGR genes has been associated with various auto- and alloimmune diseases. The aim of this study was to evaluate the association between genetic variation of FCGR and RBC alloimmunization in SCD. In this case-control study, DNA samples from 2 cohorts of transfused SCD patients were combined (France and The Netherlands). Cases had a positive history of alloimmunization, having received ≥1 RBC unit. Controls had a negative history of alloimmunization, having received ≥20 RBC units. Single nucleotide polymorphisms and copy number variation of the FCGR2/3 gene cluster were studied in a FCGR-specific multiplex ligation-dependent probe amplification assay. Frequencies were compared using logistic regression. Two hundred seventy-two patients were included (130 controls, 142 cases). The nonclassical open reading frame in the FCGR2C gene (FCGR2C.nc-ORF) was strongly associated with a decreased alloimmunization risk (odds ratio [OR] 0.26, 95% confidence [CI] 0.11-0.64). This association persisted when only including controls with exposure to ≥100 units (OR 0.30, CI 0.11-0.85) and appeared even stronger when excluding cases with Rh or K antibodies only (OR 0.19, CI 0.06-0.59). In conclusion, SCD patients with the FCGR2Cnc-ORF polymorphism have over a 3-fold lower risk for RBC alloimmunization in comparison with patients without this mutation. This protective effect was strongest for exposure to antigens other than the immunogenic Rh or K antigens.

Improving chemotherapy processes with a protocol-based information system: a pre and post-implementation study.

BACKGROUNDnThe medical application domain has been a great challenge for information technology solutions for decades, especially when the target process has been complex and multidisciplinary such as chemotherapy processes.nnnOBJECTIVEnTo evaluate the impact of a homegrown protocol based information system on the efficiency of chemotherapy workflow processes in an outpatient setting.nnnMETHODSnA day care unit of the Hematology/Oncology outpatient clinic of Erasmus Medical Center was the setting for this study. The study consisted of comparison of pre- and post-implementation of four workflow efficiency related external indicators: turn-around times of a commonly administered chemotherapy course (Paclitaxel-Carboplatin), chemotherapy course administration postponing rate, the rate of recording course administration time, and patient admission rate of the outpatient clinic. The data was gathered retrospectively from patient charts and information systems log files. For the purpose of turn-around-time 109 Paclitaxel-Carboplatin chemotherapy courses of pre-implementation were compared to 118 those of post-implementation. For the other indicators: 247 chemotherapy courses pre-implementation were compared to 324 courses post-implementation. The process maps of pre- and post-implementation were also compared to each other.nnnRESULTSnThe implementation of the system improved the process by removing repetition and sequencing of the tasks. Following the implementation, chemotherapy postponing decreased by 17.2% (Z = -4.723, P = .000) and there were 5.7% less records with missing administration time (Z =-3.047, P = .002). The admission rate increased 1.9 patient per working day (t(94) = -5.974, P = .000). The overall turn-around-time reduced 18.9 min following the implementation (t(169) = 3.48, P = .001). In a multivariate multiple regression model the reduction in turn-around time was related to the implementation of the system (Pillais Trace = 0.159, F(4,161) = 7.613, P = .000).nnnCONCLUSIONnInformation systems based on treatment protocols can reduce communication and synchronization needs between the stakeholders in a complex workflow process. These systems can help reengineering the process and improve workflow efficiency by removing unnecessary sequencing and repetitions of tasks.

N-terminal pro-B-type natriuretic peptide, tricuspid jet flow velocity, and death in adults with sickle cell disease

To the Editor: Both elevated N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels (>160 pg/mL) and elevated tricuspid regurgitant jet flow velocity (TRV 2.5 m/sec) have been related to the presence of (echocardiography defined) pulmonary hypertension and the risk of early death in patients with sickle cell disease (SCD) [1–3]. Recent guidelines advise to use NT-proBNP levels to identify patients at risk for mortality when transthoracic Doppler to measure TRV is not available [4]. We studied the relation between elevated NT-proBNP levels (>160 pg/mL), elevated TRV ( 2.5 m/sec), and the risk of mortality in a cohort of 85 adult outpatients with sickle cell anemia (HbSS) or compound heterozygous states such as HbSb-thalassemia (HbSb-thal), HbSb-thalassemia (HbSb-thal), and sickle-hemoglobin C (HbSC) [5]. Patients were excluded if they had a history of chronic obstructive pulmonary disease or poorly controlled asthma, congestive heart failure, painful crisis, or acute chest syndrome in the preceding 4 weeks and/or blood transfusion within 3 months prior to performing study related tests. The mean age at baseline analysis was 34 years (median 30; interquartile range (IQR): 23–47). We followed patients for a median of 82 months (IQR 75–85) during which three patients were lost to follow-up and 12 patients (11 HbSS and 1 HbSb-thal) died. Median age at death was 53 years (IQR 37–60). Baseline trans-thoracic echocardiographic results were available from 81 patients and echocardiography was repeated every 2 years in steady-state conditions. TRV 2.5–2.9 m/sec was considered elevated, a TRV>2.9 m/sec severely elevated, and TRV was considered normal in patients with trace or no tricuspid regurgitation (undetectable values were assigned a value of 1.3 m/sec) [1]. In 25 patients (31%) a TRV 2.5–2.9 m/sec was measured at baseline (22 (39%) HbSS/HbSb-thal and 3 (12%) HbSC/HbSb-thal patients) and a TRV >2.9 m/sec in two HbSS patients. Twenty of 56 patients with a TRV <2.5 m/sec at baseline developed an increased TRV ( 2.5 m/sec) during follow-up (5.3% per year). Having a TRV 2.5 m/sec measured at baseline did not result in a significant increased hazard rate (HR) for mortality for these patients as calculated by Cox regression analysis (HR 1.6 [confidence interval (CI) 0.5–5.2], P 5 0.4). Figure 1A. Introducing age in a multivariate Cox-regression analysis did not change the HR for mortality in patients with TRV 2.5 m/sec (HR 1.1 [CI 0.3–3.7], P 5 0.9). The HR for mortality in a subgroup of HbSS/ HbSb-thal patients with a TRV 2.5 m/sec was 1.1 [CI 0.4–3.4], P 5 0.9. Plasma NT-proBNP levels were available from 77 patients at baseline after quantitation in EDTA anticoagulated plasma employing an ELISA (Roche). In 14 patients a NTproBNP value 160 pg/mL was measured (all HbSS/HbSb-thal patients), of whom 50% also had a TRV level of 2.5 m/sec at baseline. Figure 1C. Using the previously defined cut-off value for NT-proBNP of 160 pg/mL as a risk factor for early death [6], patients with elevated NT-proBNP levels had a HR of death of 10.0 [CI 2.9–34.4], P< 0.001, compared to patients with normal NT-proBNP levels (<160 pg/mL). Figure 1B. In the HbSS/ HbSb-thal group alone this HR was 6.3 [CI 1.8–21.6], P 5 0.003. Given the low number of deaths during follow-up, a multivariate Cox-regression survival analysis was performed for only two variables at the time, always including NT-proBNP levels. None of analyzed variables that may affect NT-proBNP plasma levels (such as age, renal function, TRV, ferritin, or hemoglobin levels) could solely explain the increased HR for death for patients with NT-proBNP plasma levels of 160 pg/mL. Therefore, an elevated NT-proBNP level identifies especially HbSS/HbSb-thal patients at high risk of death independent of an elevated TRV. We hypothesize that NT-proBNP levels are likely to be determined by several prognostic factors in SCD such as diastolic dysfunction, hypoxia, age, rate of hemolysis, inflammation, renal function and iron overload. NT-proBNP might therefore be useful as a simple prognostic biomarker in the clinically asymptomatic state reflecting the severity of the generalized vasculopathy and organ dysfunction in SCD. Importantly, both the lack of an association of TRV to mortality and the relatively low mortality in our cohort, as well as in a recent European SCD cohort, are in contrast with earlier studies in the United States (US) [1–3]. As TRV was significantly related to mortality in SCD in a study of comparable size [2], our relatively small sample size is not likely to be an explanation for this conflicting observation. Also the relative low number Figure 1. Bone marrow biopsies show progression of neoplastic spindle-shaped mast cells and osteosclerosis between 2009 and 2013 with no therapy (A– B), stable disease before and after bosutinib (B–C), and response to cladribine regarding mast cells (C–D). (hematoxylin and eosin (H&E), 103 objective). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] CORRESPONDENCE

No significant prognostic value of normal precursor B-cell regeneration in paediatric acute myeloid leukaemia after induction treatment

B‐cell precursors (BCP) regeneration in bone marrow (BM) after induction chemotherapy is prognostic for good treatment response in adult acute myeloid leukaemia (AML). We detected BCP regeneration in 81% of 59 paediatric AML patients at first complete remission; this compared to 46% in an adult study. BCP regeneration did not correlate with outcome or minimal residual disease levels. In 36 healthy BM controls, BCP levels were significantly higher in children as compared to adults. Therefore, BCP regeneration does not reflect good response to treatment in paediatric AML, possibly due to the relatively high base‐line levels of BCP in children.

Effect of N-acetylcysteine on pain in daily life in patients with sickle cell disease: a randomised clinical trial

N.J.S. collected and analysed the data and wrote the manuscript; H.K. designed the study and treated patients; E.J., J.E.C, D.A.T, M.E.R., N.D., Y.A., M.K., P.K., W.G.W. and C.D.D. treated patients; C.B., D.M. and M.A.R. collected and analysed the data; F.R. designed the study, collected and analysed the data, treated patients and wrote the manuscript. All authors approved the final version of the manuscript.