Arnaud Jaccard

Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase II study.

Extranodal NK/T-cell lymphoma, nasal type, is a rare and highly aggressive disease with a grim prognosis. No therapeutic strategy is currently identified in relapsing patients. We report the results of a French prospective phase II trial of an L-asparaginase-containing regimen in 19 patients with relapsed or refractory disease treated in 13 centers. Eleven patients were in relapse and 8 patients were refractory to their first line of treatment. L-Asparaginase-based treatment yielded objective responses in 14 of the 18 evaluable patients after 3 cycles. Eleven patients entered complete remission (61%), and only 4 of them relapsed. The median overall survival time was 1 year, with a median response duration of 12 months. The main adverse events were hepatitis, cytopenia, and allergy. The absence of antiasparaginase antibodies and the disappearance of Epstein-Barr virus serum DNA were significantly associated with a better outcome. These data confirm the excellent activity of L-asparaginase-containing regimens in extranodal NK/T-cell lymphoma. L-Asparaginase-based treatment should thus be considered for salvage therapy, especially in patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma warrants evaluation in prospective trials. This trial is registered at www.clinicaltrials.gov as #NCT00283985.

Cardiac amyloidosis: Updates in diagnosis and management

Amyloidosis is a severe systemic disease. Cardiac involvement may occur in the three main types of amyloidosis (acquired monoclonal light-chain, hereditary transthyretin and senile amyloidosis) and has a major impact on prognosis. Imaging the heart to characterize and detect early cardiac involvement is one of the major aims in the assessment of this disease. Electrocardiography and transthoracic echocardiography are important diagnostic and prognostic tools in patients with cardiac involvement. Cardiac magnetic resonance imaging better characterizes myocardial involvement, functional abnormalities and amyloid deposition due to its high spatial resolution. Nuclear imaging has a role in the diagnosis of transthyretin amyloid cardiomyopathy. Cardiac biomarkers are now used for risk stratification and staging of patients with light-chain systemic amyloidosis. Different types of cardiac complications may occur, including diastolic followed by systolic heart failure, atrial and/or ventricular arrhythmias, conduction disturbances, embolic events and sometimes sudden death. Senile amyloid and hereditary transthyretin amyloid cardiomyopathy have better prognoses than light-chain amyloidosis. Cardiac treatment of heart failure is usually ineffective and is often poorly tolerated because of its hypotensive and bradycardiac effects. The three main types of amyloid disease, despite their similar cardiac appearance, have specific new aetiological treatments that may change the prognosis of this disease. Cardiologists should be aware of this disease to allow early treatment.

Efficacy of lenalidomide in POEMS syndrome: a retrospective study of 20 patients.

POEMS syndrome is a rare disorder characterized by polyneuropathy, monoclonal gammopathy, multiorgan involvement, and elevated vascular endothelial growth factor levels. Localized bone lesions require irradiation, whereas young patients with disseminated disease receive intensive treatment with stem cell support. Treatment of older and non responding patients is not yet standardized. We report the use of a combination of lenalidomide and dexamethasone in 20 patients with POEMS syndrome. Four patients were newly diagnosed, and 16 had relapsed or progressed after treatment. All but one of the patients responded: clinical improvements were noted in neuropathies (16/20) organomegaly (13/13), peripheral edema (14/15), and pulmonary hypertension (5/5). At least a very good partial response was noted in 68% of patients, with partial responses in 26%. Serum VEGF levels fell markedly in all 17 patients with available values. Twelve patients had 18‐FDG‐PET/CT at diagnosis (11 with positive findings), and nine patients during follow‐up. The number of lesions fell markedly in five cases and remained stable in two cases, while two patients became negative. During a median follow‐up of 22 months, four patients relapsed. Toxicity, predominantly hematological, was mild and manageable. Lenalidomide thus appears to be effective in POEMS syndrome, inducing high rate of clinical and biological responses. Am. J. Hematol. 88:207–212, 2013.

Differential Expression of Neurotensin and Specific Receptors, NTSR1 and NTSR2, in Normal and Malignant Human B Lymphocytes

Neurotensin, a neuropeptide growth factor, and its two specific neurotensin receptors, NTSR1 and NTSR2, were shown to be expressed by human B cell lines. Another NTSR, sortilin, which is common to neurotensin and neurotrophins, was also detected as we have previously described. Neurotensin was functional in B cell lines; it induced their proliferation and inhibited apoptosis induced by serum deprivation or Fas activation. Quantitative study of gene expression in two malignant B cell diseases showed that NTSR2 was overexpressed, NTSR1 decreased, and neurotensin was unexpressed in B cell leukemia patient’s cells, as compared with healthy B cells. However, these expressions did not significantly change in large diffuse B cell lymphoma lymph nodes compared with benign ones. This study points out that neurotensin and its two specific receptors are expressed in human B lymphocytes. Such expressions were not described, and their relationship in B cell diseases, especially in chronic B cell leukemia, needs to be considered further in regard to these findings.

Very low levels of surface CD45 reflect CLL cell fragility, are inversely correlated with trisomy 12 and are associated with increased treatment-free survival.

It has recently been suggested that the percentage of smudge cells on blood smears from patients with chronic lymphocytic leukemia (CLL) could predict overall survival. However, smudge cells are a cytological artifact influenced by multiple physical factors not related to CLL. To identify simple parameters reflecting CLL cell fragility, we studied CD45 expression in a series of 66 patients with Binet stage A CLL. Decreased CD45 expression was specific for CLL cells when compared to 44 patients with a leukemic phase of B‐cell non Hodgkin lymphoma and 42 control B‐cells. CD45 expression was markedly decreased for all patients with CLL with high percentages of smudge cells. CLL cells with the lowest CD45 expression were the most sensitive to osmotic shock. Very low levels of CD45 expression were significantly associated with lack of CD38 expression, absence of trisomy 12, and with increased treatment free survival time. Altogether, these results demonstrate that low levels of CD45 expression are specific to CLL cells and reflect cell fragility, suggesting that this is an important intrinsic biological feature that determines disease course. Am. J. Hematol. 88:747–753, 2013.

Effect of High-Cutoff Hemodialysis vs Conventional Hemodialysis on Hemodialysis Independence Among Patients With Myeloma Cast Nephropathy: A Randomized Clinical Trial

Importance Cast nephropathy is the main cause of acute kidney injury in multiple myeloma and persistent reduction in kidney function strongly affects prognosis. Strategies to rapidly remove nephrotoxic serum-free light chains combined with novel antimyeloma agents have not been evaluated prospectively. Objective To compare the hemodialysis independence rate among patients newly diagnosed with myeloma cast nephropathy treated with hemodialysis using a high-cutoff dialyzer (with very large membrane pores and high permeability to immunoglobulin light chains) or a conventional high-flux dialyzer (with small pores and lower permeability). Design, Setting, and Participants Randomized clinical trial involving 98 patients with biopsy-proven myeloma cast nephropathy requiring hemodialysis treated at 48 French centers between July 2011 and June 2016; the final date of follow-up was June 29, 2016. Interventions Intensive hemodialysis (eight 5-hour sessions over 10 days) with either a high-cutoff dialyzer (46 patients) or a conventional high-flux dialyzer (48 patients). All patients received the same chemotherapy regimen of bortezomib and dexamethasone. Main Outcomes and Measures Primary end point was hemodialysis independence at 3 months; secondary end points: hemodialysis independence rates at 6 and 12 months, hemodialysis- and chemotherapy-related adverse events, and death. Results Among 98 randomized patients, 94 (96%) (median age, 68.8 years [interquartile range, 61.2-75.3 years]; 45% women) were included in the modified intent-to-treat analysis. The hemodialysis independence rate at 3 months was 41.3% (nu2009=u200919) in the high-cutoff hemodialysis group vs 33.3% (nu2009=u200916) in the conventional hemodialysis group (between-group difference, 8.0% [95% CI, −12.0% to 27.9%], Pu2009=u2009.42); at 6 months, the rate was 56.5% (nu2009=u200926) vs 35.4% (nu2009=u200917), respectively (between-group difference, 21.1% [95% CI, 0.9% to 41.3%], Pu2009=u2009.04); and at 12 months, the rate was 60.9% (nu2009=u200928) vs 37.5% (nu2009=u200918) (between-group difference, 23.4% [95% CI, 3.2% to 43.5%], Pu2009=u2009.02). The incidence of hemodialysis-related adverse events was 43% in the high-cutoff hemodialysis group vs 39% in the conventional hemodialysis group; chemotherapy-related serious adverse events, 39% vs 37%, respectively; and at 12 months, 9 patients vs 10 patients died. Conclusions and Relevance Among patients with myeloma cast nephropathy treated with a bortezomib-based chemotherapy regimen, the use of high-cutoff hemodialysis compared with conventional hemodialysis did not result in a statistically significant difference in hemodialysis independence at 3 months. However, the study may have been underpowered to identify an early clinically important difference. Trial Registration clinicaltrials.gov Identifier: NCT01208818

CD68-positive tumor-associated macrophages predict unfavorable treatment outcomes in classical Hodgkin lymphoma in correlation with interim fluorodeoxyglucose-positron emission tomography assessment

Abstract Finding new prognostic factors to identify patients with Hodgkin lymphoma (HL) at risk of treatment resistance or relapse remains challenging in daily practice. We evaluated the relationship between CD68 expression, interim positron emission tomography (iPET) results and outcome in 158 patients with HL diagnosed from February 1995 to July 2011. Immunohistochemistry (anti-CD68) gave two groups: low with ≤ 25% positive cells (121 patients) and high with > 25% (37 patients). Five-year overall survival was higher in the low group (88.4% vs. 63.2%, p = 0.0151), as was progression-free survival (74.5% vs. 40.7%, p = 0.0003). In 68 patients evaluable, iPET correlated with CD68: 13/52 patients (25%) in the low group had positive iPET as compared to 11/16 patients (68%) in the high group (p = 0.0016). This study confirms the prognostic value of CD68 in HL. We found a correlation between CD68 and iPET suggesting potential for a better stratification.

T/B ratio does not reflect levels of ZAP70 expression in clonal CLL B-cells due to ZAP70 overexpression in patient T-cells†

Flow cytometry is the reference technique for assessing ZAP70 expression, a marker of poor prognosis in CLL. One of the most common methods is to assess ZAP70 levels in CLL cells by calculating the ratio between ZAP70 mean fluorescence intensities (MFIs) in residual T‐cells and CLL B‐cells (ZAP70 T/B ratio). In this study, we developed a new method for ZAP70 labeling. Cells were labeled with a combination of anti ZAP70 phycoerythrin‐conjugated SBZAP monoclonal antibody (mAb) and mAbs against CD45, CD19, and CD5. The latter three were used to specifically gate on different lymphocyte subsets. Staining was performed in absence (test) or in presence of excess unconjugated SBZAP mAb (isoclonic control). A so‐called ZAP70 isoclonic ratio between SBZAP MFIs in the test and isoclonic control was calculated. A series of 32 patients with CLL and 10 normal controls were studied. Prediction of IGHV mutation status by ZAP70 isoclonic and T/B ratios was similar. By using the ZAP70 isoclonic ratio, we showed that ZAP70 expression was increased in T‐cells from CLL patients. Nearly all cases with increased ZAP70 expression in CLL cells were associated with high ZAP70 expression in cognate T‐cells. Therefore, the ZAP70 isoclonic ratio was more likely to closely reflect the biology of ZAP70 dysregulation rather than the T/B ratio. These results also explained why ZAP70 T/B ratios were artefactually close to normal in cells from CLL patients with high levels of ZAP70.

Amylose systémique sénile : définition, diagnostic, pourquoi y penser ?

Senile systemic amyloidosis (SSA) is characterized by infiltration of amyloid transthyretin fibrils in the myocardium. SSA occurs mainly (but not always) in elderly men. SSA leads to hypertrophic and/or restrictive cardiomyopathy complicated by conduction disturbances, atrial arrhythmia and systemic embolization (stroke…). That is why SSA needs a special care and to be diagnosed. Cardiac SSA diagnosis needs to exclude two other forms of cardiac amyloidosis: AL amyloidosis (light chain) and hereditary transthyretin amyloidosis (genetic testing). Scintigraphic 99mTc-DPD heart retention is observed in cardiac amyloidosis. DPD heart retention is more frequent in cardiac transthyretin amyloidosis than in cardiac AL amyloidosis. Specific treatments of cardiac TTR amyloidosis are in development.

Detection of functional platelet-activating factor receptors on leukemic B cells of chronic lymphocytic leukemic patients

Although platelet-activating factor receptors (PAF-R) are reported on normal B cells, few results are available concerning leukemic ones. We demonstrated functional PAF-R on cell and nuclear surfaces of leukemic B cells of chronic lymphocytic leukemic (CLL) patients. Analysis of 102 patients revealed dramatic differences for their membrane PAF-R expression, a result that might be related to their plasma IL-4 levels. In the light of the potent immunoregulatory role of PAF on B cell physiology, it is suggested that the presence or absence of PAF-R on leukemic B cells may profoundly affect their in vivo behavior.