[Rare manifestations of monoclonal gammopathies: About two clinical cases and literature review]. / Manifestations rares des gammapathies monoclonales : à propos de 2 cas et revue de la littérature.

INTRODUCTION: Monoclonal gammopathies are common over the age of 50. Patients are usually asymptomatic. However, some patients present with secondary clinical manifestations, which are now grouped under the entity « Monoclonal Gammopathy of Clinical Significance ¼ (MGCS). CASE REPORT: Here, we report two rare cases of MGCS: an acquired von Willebrand syndrome (AvWS) and an acquired angioedema (AAE). CONCLUSION: The discovery of a decrease in von Willebrand activity (vWF:RCo) or angioedema in a patient over 50 years of age, in the absence of a family history, should prompt a search for a hemopathy and in particular, a monoclonal gammopathy.

Diffuse vertebral marrow changes at MRI: Multiple myeloma or normal?

Five MRI patterns of marrow involvement (diffuse, focal, combined diffuse and focal, variegated, and normal) are observed in patients with a marrow proliferative disorder including MM. The wide range of marrow involvement patterns in monoclonal plasma cell proliferative disorders mirrors that of their natural histories that can vary from indolent to rapidly lethal. MRI of the axial bone marrow contributes to stage these disorders, but it should not be obtained for disease detection and characterization because of its limited specificity and sensitivity. At MRI, diffuse benign hematopoietic marrow hyperplasia and marrow heterogeneities in elderly patients mimic the diffuse and variegated patterns observed in MM patients. Careful analysis of fat- and fluid-sensitive MR images and quantitative marrow assessment by using MRI and FDG-PET can contribute in differentiating these changes from those associated with neoplastic marrow infiltration, with some residual overlapping findings.

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).

Distinct factors determine the kinetics of disease relapse in adults transplanted for acute myeloid leukaemia.

BACKGROUND: Disease recurrence remains the major cause of death in adults with acute myeloid leukaemia (AML) treated using either intensive chemotherapy (IC) or allogenic stem cell transplantation (allo-SCT). AIMS: The timely delivery of maintenance drug or cellular therapies represent emerging strategies with the potential to reduce relapse after both treatment modalities, but whilst the determinants of overall relapse risk have been extensively characterized the factors determining the timing of disease recurrence have not been characterized. MATERIALS AND METHODS: We have therefore examined, using a series of sequential landmark analyses, relapse kinetics in a cohort of 2028 patients who received an allo-SCT for AML in CR1 and separately 570 patients treated with IC alone. RESULTS: In the first 3 months after allo-SCT, the factors associated with an increased risk of relapse included the presence of the FLT3-ITD (P < 0.001), patient age (P = 0.012), time interval from CR1 to transplant (P < 0.001) and donor type (P = 0.03). Relapse from 3 to 6 months was associated with a higher white cell count at diagnosis (P = 0.001), adverse-risk cytogenetics (P < 0.001), presence of FLT3-ITD mutation (P < 0.001) and time interval to achieve first complete remission (P = 0.013). Later relapse was associated with adverse cytogenetics, mutated NPM1, absence of chronic graft-versus-host disease (GVHD) and the use of in vivo T-cell depletion. In patients treated with IC alone, the factors associated with relapse in the first 3 months were adverse-risk cytogenetics (P < 0.001) and FLT3-ITD status (P = 0.001). The factors predicting later relapse were the time interval from diagnosis to CR1 (P = 0.22) and time interval from CR1 to IC (P = 0.012). DISCUSSION AND CONCLUSION: Taken together, these data provide novel insights into the biology of disease recurrence after both allo-SCT and IC and have the potential to inform the design of novel maintenance strategies in both clinical settings.

Comparative value of post-remission treatment in cytogenetically normal AML subclassified by NPM1 and FLT3-ITD allelic ratio.

Post-remission treatment (PRT) in patients with cytogenetically normal (CN) acute myeloid leukemia (AML) in first complete remission (CR1) is debated. We studied 521 patients with CN-AML in CR1, for whom mutational status of NPM1 and FLT3-ITD was available, including the FLT3-ITD allelic ratio. PRT consisted of reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (alloHSCT) (n=68), myeloablative conditioning (MAC) alloHSCT (n=137), autologous hematopoietic stem cell transplantation (autoHSCT) (n=168) or chemotherapy (n=148). Favorable overall survival (OS) was found for patients with mutated NPM1 without FLT3-ITD (71±4%). Outcome in patients with a high FLT3-ITD allelic ratio appeared to be very poor with OS and relapse-free survival (RFS) of 23±8% and 12±6%, respectively. Patients with wild-type NPM1 without FLT3-ITD or with a low allelic burden of FLT3-ITD were considered as intermediate-risk group because of similar OS and RFS at 5 years, in which PRT by RIC alloHSCT resulted in better OS and RFS as compared with chemotherapy (hazard ratio (HR) 0.56, P=0.022 and HR 0.50, P=0.004, respectively) or autoHSCT (HR 0.60, P=0.046 and HR 0.60, P=0.043, respectively). The lowest cumulative incidence of relapse (23±4%) was observed following MAC alloHSCT. These results suggest that alloHSCT may be preferred in patients with molecularly intermediate-risk CN-AML, while the choice of conditioning type may be personalized according to risk for non-relapse mortality.

Resistance prediction in AML: analysis of 4601 patients from MRC/NCRI, HOVON/SAKK, SWOG and MD Anderson Cancer Center.

Therapeutic resistance remains the principal problem in acute myeloid leukemia (AML). We used area under receiver-operating characteristic curves (AUCs) to quantify our ability to predict therapeutic resistance in individual patients, where AUC=1.0 denotes perfect prediction and AUC=0.5 denotes a coin flip, using data from 4601 patients with newly diagnosed AML given induction therapy with 3+7 or more intense standard regimens in UK Medical Research Council/National Cancer Research Institute, Dutch-Belgian Cooperative Trial Group for Hematology/Oncology/Swiss Group for Clinical Cancer Research, US cooperative group SWOG and MD Anderson Cancer Center studies. Age, performance status, white blood cell count, secondary disease, cytogenetic risk and FLT3-ITD/NPM1 mutation status were each independently associated with failure to achieve complete remission despite no early death ('primary refractoriness'). However, the AUC of a bootstrap-corrected multivariable model predicting this outcome was only 0.78, indicating only fair predictive ability. Removal of FLT3-ITD and NPM1 information only slightly decreased the AUC (0.76). Prediction of resistance, defined as primary refractoriness or short relapse-free survival, was even more difficult. Our limited ability to forecast resistance based on routinely available pretreatment covariates provides a rationale for continued randomization between standard and new therapies and supports further examination of genetic and posttreatment data to optimize resistance prediction in AML.

Comparative therapeutic value of post-remission approaches in patients with acute myeloid leukemia aged 40-60 years.

The preferred type of post-remission therapy (PRT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1) is a subject of continued debate, especially in patients at higher risk of nonrelapse mortality (NRM), including patients >40 years of age. We report results of a time-dependent multivariable analysis of allogenic hematopoietic stem cell transplantation (alloHSCT) (n=337) versus chemotherapy (n=271) or autologous HSCT (autoHSCT) (n=152) in 760 patients aged 40-60 years with AML in CR1. Patients receiving alloHSCT showed improved overall survival (OS) as compared with chemotherapy (respectively, 57±3% vs 40±3% at 5 years, P<0.001). Comparable OS was observed following alloHSCT and autoHSCT in patients with intermediate-risk AML (60±4 vs 54±5%). However, alloHSCT was associated with less relapse (hazard ratio (HR) 0.51, P<0.001) and better relapse-free survival (RFS) (HR 0.74, P=0.029) as compared with autoHSCT in intermediate-risk AMLs. AlloHSCT was applied following myeloablative conditioning (n=157) or reduced intensity conditioning (n=180), resulting in less NRM, but comparable outcome with respect to OS, RFS and relapse. Collectively, these results show that alloHSCT is to be preferred over chemotherapy as PRT in patients with intermediate- and poor-risk AML aged 40-60 years, whereas autoHSCT remains a treatment option to be considered in patients with intermediate-risk AML.

Lenalidomide in relapsed refractory myeloma patients: impact of previous response to bortezomib and thalidomide on treatment efficacy. Results of a medical need program in Belgium.

The prognosis of multiple myeloma patients has significantly improved since the introduction of the novel agents thalidomide, bortezomib and lenalidomide. We report the data of a medical need programme with lenalidomide plus dexamethasone, conducted in Belgium between August 2007 and March 2008, and including 98 relapsed refractory multiple myeloma patients. In addition to chemotherapy and steroids, all patients had received prior treatment with bortezomib, and 84% of them had been exposed to thalidomide. In 52 patients response data could be retrieved by post-hoc analysis. A partial remission or better was achieved in 52% (49% partial and 3% complete response) of patients, despite a median of 5 previous anti-myeloma treatment lines. Responses were rapid while the majority of patients received lenalidomide with once weekly (also called low-dose) dexamethasone. Treatment with lenalidomide plus dexamethasone did prolong overall survival by nearly half a year in this population with end-stage myeloma. Overall response and quality of response were independent of previous response to thalidomide and bortezomib, although the time to progression tended to be shorter in thalidomide- and bortezomib-refractory patients. It can be concluded that lenalidomide plus dexamethasone is an effective and safe treatment regimen in highly refractory multiple myeloma patients, and that these responses are irrespective of previous exposure or sensitivity to thalidomide and bortezomib.

The Belgian 2010 consensus recommendations for the treatment of multiple myeloma.

Since the introduction of novel therapeutic agents including thalidomide, lenalidomide and bortezomib, the prognosis of multiple myeloma (MM) has significantly improved. These agents have been incorporated into numerous treatment schedules for newly diagnosed as well as more advanced MM patients. Hence, the therapeutic options for MM have become more complex and subject to rapid changes. The multiple myeloma study group (MMSG) of the Belgian Hematological Society has established recommendations for the treatment of MM as based on an extensive review of the literature which is also summarized in this paper. The recommendations are the result of a consensus opinion between haematologists with experience in the field and representing most haematology centres in Belgium. Where applicable, reimbursement criteria are also taken into account. The consensus recommendations should be a reference for use by clinical haematologists in daily practice.

Characteristics of secondary acute lymphoblastic leukemia with L3 morphology in adult patients.

Secondary acute lymphoblastic leukemia (sALL) is an uncommon condition and sALL with L3 morphology is still less frequent. Here, we compare the characteristics of available cases of L3 sALL (16 patients, including 12 previously published cases and 4 personal cases) to those of de novo L3 ALL and of non L3 sALL. Two patients with L3 sALL obtained a CR after aggressive treatment of their leukemia. Compared with 24 patients from the literature with de novo L3 ALL, L3 sALL patients were characterized by an older age (median 46 vs. 29.5 years, p = 0.0003) and by a poor prognosis (complete responses: 2/16 vs. 19/24, p = 0.0001, median survival: 0.46 month vs. undetermined, p < 0.0001). In comparison with 19 patients from the literature with non L3 sALL, L3 sALL patients were characterized by a high Male/Female ratio (14/2 vs. 8/11, p = 0.01), a frequent history of Hodgkin's disease (12/16 vs. 7/19, p = 0.04) and, again, by a poor prognosis (complete responses: 2/16 vs. 13/18, p = 0.0001, median survival 0.46 vs. 13 months, p = 0.001). In conclusion, though based on a small group of heterogeneously treated patients, some characteristics of L3 sALL, seem to emerge, compared both with de novo L3 ALL and with non L3 sALL, the most prominent being its extremely poor prognosis.

Nuclear oncology and the Imagene concept.

Over the past 2 decades we have witnessed an explosion of new radioisotopic tracers aimed at detecting, staging and eventually treating tumors. In fact, nuclear oncology has evolved into a field on its own. Aside from aspecific radioisotopic tracers such as thallium 201 or gallium 67, clinicians and oncologists can now use specific radiolabeled monoclonal antibodies and metabolic tracers. In the near future, molecular probes based on the sequencing of the human genome with an exquisite specificity should also become available. In this article, we shall review the most recent developments in this new field.

Dynamic antral scintigraphy to characterize gastric antral motility in functional dyspepsia.

UNLABELLED: We evaluated intragastric food distribution and antral motor activity in patients with functional dyspepsia. METHODS: A standard gastric emptying test and dynamic imaging of the antrum were used to characterize gastric antral motility disturbances and to correlate them with total and compartmental gastric emptying in 25 dyspeptic patients. RESULTS: We found a 40% prevalence of gastroparesis in functional dyspepsia. Solid gastric emptying delay is indicated by a prolonged lag phase and an increase in frequency and amplitude of gastric contractions, resulting in nonexpulsive antral contractions and/or antropyloric dyscoordination. Food retention in the distal stomach and antral distention appears to account for patients' dyspeptic symptoms. CONCLUSION: This study demonstrates that scintigraphy not only detects abnormalities of food distribution in the stomach but also provides information on antral motor activity noninvasively. Dynamic antral scintigraphy and compartmental gastric emptying are useful tools to define the pathophysiology of dyspeptic patients with or without gastroparesis.

Scintigraphic imaging of oncogenes with antisense probes: does it make sense?

Based on the specificity of the Watson-Crick base pairing formation, antisense deoxyoligonucleotides have been used to inhibit the expression of oncogenes in various cancer cells. Activation of an oncogene by means of amplification leads to an increased, detectable amount of the mRNA transcript in the cytoplasm. The aim of this study was to demonstrate that cells which are expressing a particular mRNA transcript do preferentially and specifically retain the antisense probe targeting that mRNA. Using a mouse plasmacytoma cell line (MOPC315) which produces high levels of IgA heavy chain mRNA, a control mouse pre B cell line (7OZ/3B), a human mammary cell line (MCF7) which expresses the erbB2 or neu oncogene, MOPC315 cells as neu-negative controls, and antisense DNA oligonucleotides complementary to the 5' region of the mRNAs and the sense sequence, we have shown that there is a preferential, specific retention of the IgA and neu antisense sequence in MOPC315 and MCF7 cells, respectively. We have further demonstrated that this retention is time and concentration dependent with a maximum at 24 h. We conclude that cancer cells which express a particular oncogene are suitable targets for radiolabeled antisense deoxyoligonucleotides directed toward the oncogene transcript. This work and recent developments in the antisense field lead to the expectation of a new class of radiopharmaceuticals with unique specificity.

Outcome following organ removal from poisoned donors: experience with 12 cases and a review of the literature.

From 1975 to 1993, our University Hospital performed 2789 graft procedures. During the same period, 12 poisoned, "brain-dead" patients were considered as organ donors. The toxic substances involved were: methaqualone (n = 1), benzodiazepine alone (n = 1), benzodiazepine plus tricyclic antidepressants (n =1), tricyclic antidepressants alone (n = 1), barbiturates (n = 2), insulin (n = 2), carbon monoxide (n = 1), cyanide (n = 1), methanol (n = 1), and acetaminophen (n = 1). From these intoxicated persons, 32 organ transplants were obtained, but only 23 could be followed for 1 month and only 20 for 1 year. The outcome at 1 month was favorable in 20 of the 23 patients. Two heart transplant patients died with 24h after grafting from stroke and acute heart failure, respectively. Preoperative hepatic encephalopathy was not corrected after grafting and was directly responsible for the death of a liver transplant patient. After 1 year, 15 of the 20 recipients were still alive. Chronic hepatic graft rejection led to a fatal outcome in one recipient and to second grafting in another. Finally, one recipient died from delayed neoplasia. Based on our experience, organ procurement may be considered in a few select cases of acute poisoning. Attention should, however, be drawn to possible graft damage due to some poisons.