Mark-David Levin

Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK)

An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in this population. Elderly patients with AML were randomly assigned in this phase 2 study (n = 171) to receive standard chemotherapy (3 + 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m(2) twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P = .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n = 63) compared with the control arm (n = 28; P = .043), but the percentages of death or life-threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). The results of the present study show that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR904 in The Nederlands Trial Register (www.trialregister.nl).

Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma.

The combination of melphalan, prednisone, and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma who are ineligible for stem cell transplantation. Long-term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone, and lenalidomide, followed by lenalidomide maintenance therapy, showed promising results without severe neuropathy emerging. We randomly assigned 668 patients between nine 4-week cycles of MPT followed by thalidomide maintenance until disease progression or unacceptable toxicity (MPT-T) and the same MP regimen with thalidomide being replaced by lenalidomide (MPR-R). This multicenter, open-label, randomized phase 3 trial was undertaken by Dutch-Belgium Cooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group (the HOVON87/NMSG18 trial). The primary end point was progression-free survival (PFS). A total of 318 patients were randomly assigned to receive MPT-T, and 319 received MPR-R. After a median follow-up of 36 months, PFS with MPT-T was 20 months (95% confidence interval [CI], 18-23 months) vs 23 months (95% CI, 19-27 months) with MPR-R (hazard ratio, 0.87; 95% CI, 0.72-1.04; P = .12). Response rates were similar, with at least a very good partial response of 47% and 45%, respectively. Hematologic toxicity was more pronounced with MPR-R, especially grades 3 and 4 neutropenia: 64% vs 27%. Neuropathy of at least grade 3 was significantly higher in the MPT-T arm: 16% vs 2% in MPR-R, resulting in a significant shorter duration of maintenance therapy (5 vs 17 months in MPR-R), irrespective of age. MPR-R has no advantage over MPT-T concerning efficacy. The toxicity profile differed with clinically significant neuropathy during thalidomide maintenance vs myelosuppression with MPR.

The transferrin/log(ferritin) ratio: a new tool for the diagnosis of iron deficiency anemia

Abstract Background: Serum ferritin is the best single laboratory test to diagnose iron deficiency anemia (IDA). Ferritin levels <20 μg/L are highly specific for IDA, and ferritin levels >100 μg/L usually exclude IDA. However, ferritin concentrations between 20 and 100 μg/L are often inconclusive. The objective of this study was to improve the diagnosis of IDA when ferritin levels are inconclusive. Methods: We evaluated the predictive performance of classic (ferritin, mean corpuscular volume, transferrin and serum iron) and modern [reticulocyte hemoglobin content, serum transferrin receptor and soluble transferrin receptor (sTfR)/log(ferr)] iron status parameters to diagnose IDA in 2084 anemic, non-hospitalized patients. The results were validated in an independent cohort of 274 anemic patients. Results: In our study population, 29% (595 patients) of the patients had a ferritin level between 20 and 100 μg/L, hampering diagnosis of IDA. None of the classic or modern parameters was capable of completely separating the IDA population from the non-IDA population. However, using a new parameter, the transferrin/log(ferritin) ratio, the IDA and non-IDA populations can be completely separated. At a cut-off value of 1.70, the transferrin/log(ferritin) ratio indicates IDA in 29% of the patients with inconclusive ferritin levels. Conclusions: The transferrin/log(ferritin) ratio is a practical new tool that improves diagnosis of iron deficiency when ferritin levels are inconclusive.

Screening for alloantibodies in the serum of patients receiving platelet transfusions: a comparison of the ELISA, lymphocytotoxicity, and the indirect immunofluorescence method

BACKGROUND : For screening of alloimmunization in patients repeatedly receiving platelet transfusions, different tests are used, none of which is the standard. Here we describe a comparison of four tests most commonly used for detection of alloimmunization in a group of nonselected patients receiving platelet transfusions.

Screening for gastrointestinal malignancy in patients with iron deficiency anemia by general practitioners: An observational study

Abstract Background. The prevalence of iron deficiency anemia (IDA) is 2–5% in men and postmenopausal women in the developed world. IDA is commonly caused by chronic gastrointestinal blood loss, and a thorough examination of the gastrointestinal tract must be standard practice. Objective. To retrospectively study endoscopic evaluations of patients from general practitioners diagnosed with IDA in a peripheral hospital laboratory in order to determine the cause of IDA and the number of gastrointestinal malignancies. Material and methods. We retrospectively evaluated all patients with IDA diagnosed in a peripheral hospital laboratory by the general practitioner in the region of our hospital from 1 January 2004 until 31 December 2005. We included women older than 50 and men 18 years and older without a history of IDA in the previous 2 years. Results. In 2 years, 287 patients were newly diagnosed with IDA in our hospital laboratory. Only 90 (31%) patients were endoscopically evaluated within 4 months. Gastrointestinal endoscopy revealed at least one lesion potentially responsible for blood loss in 41 of 90 (46%) patients. The most common lesions identified by gastroduodenal endoscopy were erosive esophagitis, gastritis and duodenitis (14%). Cancer was the most commonly detected lesion in the colon, accounting for 17 of 21 colonic lesions explaining IDA. In total, gastrointestinal malignancy was diagnosed in 2% of screened patients. Factors determining the decision for endoscopic screening were lower hemoglobin level, lower ferritin level and male gender. Conclusion. In our retrospective study of patients with IDA, only 31% received any form of endoscopic evaluation. In general practice, IDA is investigated suboptimally, and interventions other than the issuing of guidelines are needed to change practice.

Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma.

The prognosis of multiple myeloma (MM) patients who become refractory to lenalidomide and bortezomib is very poor, indicating the need for new therapeutic strategies for these patients. Next to the development of new drugs, the strategy of combining agents with synergistic activity may also result in clinical benefit for patients with advanced myeloma. We have previously shown in a retrospective analysis that lenalidomide combined with continuous low-dose cyclophosphamide and prednisone (REP) had remarkable activity in heavily pretreated, lenalidomide-refractory MM patients. To evaluate this combination prospectively, we initiated a phase 1/2 study to determine the optimal dose and to assess its efficacy and safety in lenalidomide-refractory MM patients. The maximum tolerated dose (MTD) was defined as 25 mg lenalidomide (days 1-21/28 days), combined with continuous cyclophosphamide (50 mg/d) and prednisone (20 mg/d). At the MTD (n = 67 patients), the overall response rate was 67%, and at least minimal response was achieved in 83% of the patients. Median progression-free survival and overall survival were 12.1 and 29.0 months, respectively. Similar results were achieved in the subset of patients with lenalidomide- and bortezomib-refractory disease as well as in patients with high-risk cytogenetic abnormalities, defined as t(4;14), t(14;16), del(17p), and/or ampl(1q) as assessed by fluorescence in situ hybridization. Neutropenia (22%) and thrombocytopenia (22%) were the most common grade 3-4 hematologic adverse events. Infections (21%) were the most common grade 3-5 nonhematologic adverse events. In conclusion, the addition of continuous low-dose oral cyclophosphamide to lenalidomide and prednisone offers a new therapeutic perspective for multidrug refractory MM patients. This trial was registered at www.clinicaltrials.gov as #NCT01352338.

Influence of C-reactive protein levels and age on the value of D-dimer in diagnosing pulmonary embolism

Recently, the number of performed CT‐angiographies to diagnose pulmonary embolism (PE) rised markedly, while the incidence of PE hardly increased. This low yield of CT‐angiography leads to more patients exposed to radiation and higher costs.

Phase I/II trial of weekly bortezomib with lenalidomide and dexamethasone in first relapse or primary refractory myeloma

The use of the proteasome inhibitor bortezomib and immunomodulatory drugs such as thalidomide and lenalidomide have markedly improved outcome in patients with multiple myeloma (MM).[1][1] However, the majority of patients will eventually relapse, necessitating salvage therapy. HOVON 86 is a dose

First‐Line Palliative HER2‐Targeted Therapy in HER2‐Positive Metastatic Breast Cancer Is Less Effective After Previous Adjuvant Trastuzumab‐Based Therapy

BACKGROUND Survival of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC) has improved dramatically since trastuzumab has become available, although the disease eventually progresses in most patients. This study investigates the outcome (overall survival [OS] and time to next treatment [TNT]) in MBC patients pretreated with trastuzumab in the adjuvant setting (TP-group) compared with trastuzumab-naïve patients (TN-group) in order to investigate the possibility of trastuzumab resistance. PATIENTS AND METHODS Patients treated with first-line HER2-targeted-containing chemotherapy were eligible for the study. A power analysis was performed to estimate the minimum size of the TP-group. OS and TNT were estimated using Kaplan-Meier curves and multivariable Cox proportional hazards models. RESULTS Between January 1, 2000, and June 1, 2014, 469 patients were included, of whom 82 were in the TP-group and 387 were in the TN-group. Median OS and TNT were significantly worse in the TP-group compared with the TN-group (17 vs. 30 months, adjusted hazard ratio [HR] 1.84 [1.15-2.96], p = .01 and 7 vs. 13 months, adjusted HR 1.65 [1.06-2.58], p = .03) after adjustment for age, year of diagnosis, disease-free interval, hormone receptor status, metastatic site, and cytotoxic regimens. CONCLUSION First-line trastuzumab-containing treatment regimens are less effective in patients with failure of adjuvant trastuzumab compared with trastuzumab-naïve patients and might be due to trastuzumab resistance. The impact of trastuzumab resistance on the response on dual HER2 blockade with trastuzumab and pertuzumab and how resistance mechanisms can be used in the optimization of HER2-targeted treatment lines need further investigation. IMPLICATIONS FOR PRACTICE Evidence on the efficacy of palliative trastuzumab-based therapy after failure of trastuzumab in the adjuvant setting is limited because of a minority of patients treated with adjuvant trastuzumab in clinical trials. In this study, less clinical benefit of palliative trastuzumab-based therapy was observed in patients relapsing after adjuvant trastuzumab compared with no adjuvant trastuzumab treatment. Subgroup analyses and multivariable analyses revealed that this was independent of possible confounding factors, including adjuvant taxane-treatment. This might suggest a clinically meaningful impaired efficacy of trastuzumab after previous, in this case adjuvant, trastuzumab therapy. These results could have implications for treatment decision-making after short progression-free intervals on trastuzumab-containing regimens in the palliative setting.

Interlaboratory Reproducibility of Blood Morphology Using the Digital Microscope

Differential counting of peripheral blood cells is an important diagnostic tool. However, manual morphological analysis using the microscope is time-consuming and requires highly trained personnel. The digital microscope is capable of performing an automated peripheral blood cell differential, which is as reliable as manual classification by experienced laboratory technicians. To date, information concerning the interlaboratory variation and quality of cell classification by independently operated digital microscopy systems is limited. We compared four independently operated digital microscope systems for their ability in classifying the five main peripheral blood cell classes and detection of blast cells in 200 randomly selected samples. Set against the averaged results, the R2 values for neutrophils ranged between 0.90 and 0.96, for lymphocytes between 0.83 and 0.94, for monocytes between 0.77 and 0.82, for eosinophils between 0.70 and 0.78, and for blast cells between 0.94 and 0.99. The R2 values for the basophils were between 0.28 and 0.34. This study shows that independently operated digital microscopy systems yield reproducible preclassification results when determining the percentages of neutrophils, eosinophils, lymphocytes, monocytes, and blast cells in a peripheral blood smear. Detection of basophils was hampered by the low incidence of this cell class in the samples.