Minor clone provides a reservoir for relapse in multiple myeloma.

Recent studies have provided direct evidence for genetic variegation in subclones for various cancer types. However, little is known about subclonal evolutionary processes according to treatment and subsequent relapse in multiple myeloma (MM). This issue was addressed in a cohort of 24 MM patients treated either with conventional chemotherapy or with the proteasome inhibitor, bortezomib. As MM is a highly heterogeneous disease associated with a large number of chromosomal abnormalities, a subset of secondary genetic events that seem to reflect progression, 1q21 gain, NF-κB-activating mutations, RB1 and TP53 deletions, was examined. By using high-resolution single-nucleotide polymorphism arrays, subclones were identified with nonlinear complex evolutionary histories. Such reordering of the spectrum of genetic lesions, identified in a third of MM patients during therapy, is likely to reflect the selection of genetically distinct subclones, not initially competitive against the dominant population but which survived chemotherapy, thrived and acquired new anomalies. In addition, the emergence of minor subclones at relapse appeared to be significantly associated with bortezomib treatment. These data support the idea that new strategies for future clinical trials in MM should combine targeted therapy and subpopulations' control to eradicate all myeloma subclones in order to obtain long-term remission.

Efficacy of bendamustine in relapsed/refractory myeloma patients: results from the French compassionate use program.

One hundred and ten patients with multiple myeloma were treated with bendamustine as part of a French compassionate use program. To receive bendamustine, patients had to present with relapsed or refractory disease after prior therapies that had to include alkylators, steroids, IMiDs and bortezomib. The median number of bendamustine cycles administered was 4 (1-13). The overall response rate (≥ partial response) was 30%, including 2% complete responses. The median progression-free and overall survival for the entire cohort were 9.3 and 12.4 months, respectively. In this series of patients with advanced disease, both the response rate and the duration of response are encouraging and indicate that bendamustine presents a feasible option, which should be considered for the treatment of relapsed/refractory patients.

Haemophagocytic syndrome associated with infections.

Haemophagocytic syndromes (HS) are the clinical manifestation of an increased macrophagic activity with haemophagocytosis. Pathophysiology is related to a deregulation of T-lymphocytes and excessive production of cytokines. The main clinicobiological features are fever, hepatosplenomegaly, adenopathies, skin rash, neurological features, cytopenias, hypertriglyceridaemia, hyperferritinaemia and coagulopathy. Diagnosis is based on examination of the bone marrow which shows benign histiocytes actively phagocytosing haemopoietic cells. Acquired HS are mostly associated with an underlying disease such as immunodeficiency, haematological neoplasias and autoimmune diseases. Infection-associated HS was originally described by Risdall in 1979, in viral disease. Since the initial description HS has also been documented in patients with bacterial, parasitic or fungal infections. Epstein-Barr virus (EBV) is the causative agent in most cases. In EBV-associated HS, which sometimes has a fatal course, unregulated T-cell reaction or uncontrolled B-cell proliferation may release cytokines. Management of HS consists of early diagnosis, careful screening for, and prompt treatment of, infections and detection and therapy of any underlying disease. Prognosis of infection-associated haemophagocytic syndrome (IAHS) is better than that in other types of secondary HS. Management of cytokine imbalance should be useful to improve the outcome and reduce the mortality rate in these cases.

[Fusaria infection in patients with neutropenia: apropos of 3 cases]. / Infection fusariale chez le neutropénique: à propos de trois observations.

The authors report three cases of fusarial infection in neutropenic patients with hematologic malignancies. The first patient was affected by a cutaneous extensive fusariosis. The second patient developed a fusarial lung infection during a multiple organ failure following allogenic bone marrow transplantation. The third patient who presented with refractory acute myelogenous leukemia, developed fusarial skin lesions, and died from pulmonary failure. The treatment of fusarial infection is disappointing and requires amphotericin B, in association with hematopoietic growth factors. The role of new agents, or combination chemotherapy remains to be determinated. The recovery of adequate neutrophil levels is the most important factor in the resolution of fusarial infection.

[Hemophagocytic syndromes. A series of 23 cases]. / Syndromes hémophagocytaires. Une série de 23 observations.

Inappropriate macrophage activation is responsible for clinical, biological and histological features characterized by diffuse non malignant histiocytic tissue infiltration called "reactive hemophagocytic syndrome" (RHS). We report here 23 new cases. Immunodepression (10 cases), hematologic malignancies (13 cases) and infection (10 cases) are the most favorable conditions associated with RHS. In many cases, several conditions were present at time of diagnosis of RHS and increased its severity. Mechanisms of RHS remains unclear, but cytokine may play a role. Outcome is variable, but death is the most common issue (17 deaths in our series related to RHS). Corticosteroids, etoposide can improve some situations. Further study is needed to establish the role of cyclosporine A or allogenic bone marrow transplantation.

[Empirical treatment of febrile episodes in granulocytopenic patients with a combination of piperacillin and ofloxacin. Preliminary study]. / Traitement empirique des épisodes fébriles chez les patients granulopéniques par l'association pipéracilline-ofloxacine. Etude préliminaire.

We evaluated the efficacy and toxicity of piperacillin-ofloxacin as an empiric treatment of fever in patients with neutropenia. 24 febrile episodes occurring in 21 patients (mean neutropenia: 204/mm3) were treated. The neutropenia was due to an hematologic malignancy in 6 cases and to chemotherapy in 15 cases. Fever was related to septicemia in 4 cases, urinary tract infection in 1 case, other infectious sites without microbiological documentation in 11 cases, and was of unknown origin in 8 cases. Empirical therapy was started within 24 hours of the occurrence of fever greater than 38.5 degrees C with the combination of intravenous piperacillin (12 g/day in 3 divided doses) and oral ofloxacin (400 mg/day in 2 doses). The overall response rate was 86% (19/22) of evaluable cases, with an immediate success rate (apyrexia within 48 hours) of 46%. Of the 3 failures, one was bacteriologically documented and was due to a multiply resistant strain of Staphylococcus haemolyticus (to which both piperacillin and ofloxacin were resistant). The therapy was clinically well tolerated in all except 3 patients, in whom intolerance to intravenous piperacillin was observed, leading to discontinuation of the drug in 2 cases. More extensive and comparative trials should better determine the place of this piperacillin-ofloxacin combination as first-line treatment of febrile episodes in patients with neutropenia.