FDG-PET/CT findings in systemic mastocytosis: a French multicentre study.

INTRODUCTION: Mastocytosis is a clonal haematological disease characterized by uncontrolled proliferation and the activation of mast cells. The value of FDG-PET/CT (FDG-PET) in mastocytosis has yet to be determined. METHODS: We retrospectively identified patients with an established diagnosis of systemic mastocytosis (SM), according to the WHO criteria, who underwent PET using the French Reference Centre for Mastocytosis database. Semi-quantitative and visual analysis of FDG-PET was performed and compared to the clinico-biological data. RESULTS: Our cohort included 19 adult patients, median age 65 years [range 58-74], including three with smouldering SM (SSM), three with aggressive SM (ASM), 10 with an associated clonal haematological non-mast-cell lineage disease (SM-AHNMD), and three with mast cell sarcoma (MCS). FDG-PET was performed at the time of the SM diagnosis (15/19), to evaluate lymph node (LN) activity (3/19) or the efficacy of therapy (1/19). FDG uptake was observed in the bone marrow (BM) (9/19, 47%), LN (6/19, 32%), spleen (12/19, 63%), or liver (1/19, 5%). No significant FDG uptake was observed in the SSM and ASM patients. A pathological FDG uptake was observed in the BM of 6/10 patients with SM-AHNMD, appearing as diffuse and homogeneous, and in the LN of 5/10 patients. All 3 MCS patients showed intense and multifocal BM pathological uptake, mimicking metastasis. No correlation was found between the FDG-PET findings and serum tryptase levels, BM mast cell infiltration percentage, and CD30 and CD2 expression by mast cells. CONCLUSIONS: FDG uptake does not appear to be a sensitive marker of mast cell activation or proliferation because no significant FDG uptake was observed in most common forms of mastocytosis (notably purely aggressive SM). However, pathological FDG uptake was observed in the SM-AHNMD and in MCS cases, suggesting a role of FDG-PET in their early identification and as a tool of therapeutic assessment in this subgroup of patients.

Heavy/light chain specific immunoglobulin ratios provides no additional information than serum proteins electrophoresis and immunofixation for the diagnosis and the follow-up of intact immunoglobulin multiple myeloma patients.

BACKGROUND: Serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) are used for diagnosis and follow-up of patients with intact immunoglobulin multiple myeloma. However, the numerous limitations of these methods led to the development of a nephelometric immunoassay (Hevylite™) for the specific measurement of serum IgGκ, IgGλ, IgAκ and IgAλ concentrations. METHODS: In this study, we evaluated the correlation between this assay and SPE and IFE in 114 sera of 15 patients (12 IgG and 3 IgA patients) and its impact on the clinical care of patients, especially for diagnosis, for the evaluation of residual disease and for early detection of relapse. RESULTS: At inclusion and during follow-up, we found a good correlation between monoclonal immunoglobulin concentrations and SPE (R(2)=0.902 for IgA and R(2)=0.915 for IgG) and nephelometric quantification (R(2)=0.948 for IgA and R(2)=0.920 for IgG) for the evaluation of monoclonal and polyclonal immunoglobulins. Our results illustrate that the Hevylite™ test is less sensitive than the IFE for detection of residual disease: 5 patients who obtained very good partial response or complete response had normalization of the Hevylite™ ratio while IFE was still positive. A relapse had been detectable with the Hevylite™ ratio 1 to 2 months earlier than with SPE and IFE in 3 patients out of 15, but no recommendations for treating patients with only slight biological relapse are available. CONCLUSION: Our results demonstrate that heavy/light chain specific immunoglobulin ratios provides no additional information than serum proteins electrophoresis and immunofixation for the diagnosis and the follow-up of intact immunoglobulin multiple myeloma patients. We also studied the correlation between the concentration of total immunoglobulin measured by Hevylite™ (sum of Ig'κ + Ig'λ) and nephelometric measurement of total IgG or IgA. For this correlation analysis, all 114 sera were analyzed. The correlation coefficient was R(2) = 0.948 for IgA and R(2) = 0.920 for IgG.

Vertebral fractures in Gaucher disease type I: data from the French "Observatoire" on Gaucher disease (FROG).

UNLABELLED: Gaucher disease type 1 (GD1), results in a range of skeletal complications including osteopenia, osteoporosis, and osteonecrosis, but there is little published information regarding vertebral fractures. Findings from this observational study indicated that the prevalence of vertebral fractures in a cohort of adult French GD1 patients is approximately 15%. INTRODUCTION: The aim of the study was to assess the prevalence and characteristics of vertebral fractures in a cohort of adult patients with GD1. METHODS: This study was performed in adult patients with GD1 based on a detailed and complete clinical examination. For all patients for whom vertebral fractures were reported, a specific questionnaire was sent to physicians, and imaging data were collected, when available, for centralized analysis. RESULTS: Data were collected from a total of 105 adult GD1 patients. Bone complications were reported in 85% of patients, among whom vertebral fractures were diagnosed in 16 (15%); seven women and nine men (mean age, 45 years). We observed five patients with multiple vertebral fractures and one patient in whom the T3 vertebra was fractured. Most of these patients did not report fracture-related back pain. CONCLUSIONS: The prevalence of vertebral fractures in this cohort of adult patients with GD1 was 15%. Greater awareness of the natural history of vertebral fractures in GD1, and rigorous monitoring of bone fragility and spine involvement in affected patients, should allow earlier detection and initiation of treatment tailored toward improving bone status.

The neurological manifestations of Gaucher disease type 1: the French Observatoire on Gaucher disease (FROG).

BACKGROUND: Gaucher disease (GD), the most prevalent inherited lysosomal storage disorder, is caused by deficient glucocerebrosidase activity. Type 1 GD (GD1), the most common variant, is classically considered non-neuronopathic. METHODS: We performed a national cross-sectional observational survey-the French Observatoire on Gaucher Disease (FROG)-in patients with GD1 between March 2005 and September 2006. The study included all patients over 18 years of age with confirmed GD1 who attended participating centers for regular follow-up. RESULTS: One hundred and five patients were included, in whom we studied the prevalence and characteristics of relevant neurological symptoms associated with the neuraxis. Of these, 51 (49%) GD1 patients presented at least one neurological symptom. Four patients (4%) had Parkinson disease and 22 (21%) presented with at least one parkinsonian sign or at least one sign frequently associated with Parkinson disease. Five patients (5%) had a previous diagnosis of peripheral neuropathy. Other central nervous system symptoms were recorded in 20 (19%) patients and other peripheral nervous system symptoms in 39 (37%) patients. CONCLUSIONS: These data challenge the current classification of GD, and suggest that the three forms of GD each involve a different profile of neurological manifestations.

[Gaucher's disease in Rennes University hospital: a 10-year retrospective study]. / Etude rétrospective sur dix ans des patients atteints de maladie de Gaucher au CHU de Rennes.

INTRODUCTION: Gaucher's disease (GD) remains rare and cohort studies are essential to improve our knowledge of this disease. METHODS: We performed a 10-year retrospective study of patients with GD followed-up in the Rennes University teaching hospital. RESULTS: Among a population of 1,500,000 inhabitants, 12 patients with GD were identified. Eight were men, and four were women. Mean age at diagnosis was 32.3 years and the first symptoms appeared around 31 years old. Main symptoms were: splenomegaly (82%), hepatomegaly (64%), thrombocytopenia (73%), anemia (64%), deterioration of general status (45%), bone pain (27%). Parkinsonism was noted in two patients, polyclonal gammopathy in two others, and monoclonal gammopathy was evidenced in four patients, with chronic lymphocytic lymphoma in one of them. Enzymatic activity dosage confirmed the diagnosis of GD for eight patients. For the remaining four patients, diagnosis was obtained by identification of Gaucher's cells on tissue examination. Substitutive enzymotherapy (SE) was performed for seven patients, with great improvement of initial symptoms. For two of these seven patients, SE is changed for miglustat with persistent improvement of clinical status. CONCLUSION: Association between GD and Parkinsonism or between GD and gammopathy was confirmed in our study. Other cohort studies are needed to improve the knowledge of GD.

Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials.

One hundred de novo multiple myeloma patients with t(4;14) treated with double intensive therapy according to IFM99 protocols were retrospectively analyzed. The median overall survival (OS) and event-free survival (EFS) were 41.4 and 21 months, respectively, as compared to 65 and 37 for patients included in the IFM99 trials without t(4;14) (P<10(-7)). We identified a subgroup of patients presenting at diagnosis with both low beta(2)-microglobulin <4 mg/l and high hemoglobin (Hb) >/=10 g/l (46% of the cases) with a median OS of 54.6 months and a median EFS of 26 months, respectively, which benefits from high-dose therapy (HDT); conversely patients with one or both adverse prognostic factor (high beta(2)-microglobulin and/or low Hb) had a poor outcome. The achievement of either complete response or very good partial response after HDT was also a powerful independent prognostic factor for both OS and EFS.

Effect of treatment on biclonal gammopathy associated with Gaucher disease.

The non-random association of Gaucher disease with polyclonal and monoclonal gammopathy has been known since 1950. The effect of treatment on monoclonal gammopathy is not well documented. We report on the long-term evolution of a biclonal gammopathy in a patient with type I Gaucher disease who was treated with splenectomy and enzyme replacement therapy. A 44-year-old man presented with hepatomegaly and massive splenomegaly. Bone marrow aspirate contained typical Gaucher cells and beta-glucosidase was low in peripheral blood leukocytes. Mutations N370S and R120W were detected. Serum protein electrophoresis disclosed two spikes in gammaglobulins. Immunofixation identified two monoclonal components: IgG kappa and IgA kappa. Gammaglobulin concentration was 31.6 g/L. A splenectomy was performed on September 2003 because of massive splenomegaly (9500 g). Two months after the splenectomy, gammaglobulin concentration was 25.2 g/L. Enzyme replacement therapy (Cerezyme 45 UI/kg every two weeks) was prescribed from April 2004 because of significant hepatomegaly and cholestasis. In April 2007 (3 years after the beginning of treatment), serum electrophoresis showed the persistence of two spikes with gammaglobulin concentration at 20.5 g/L. Simultaneously, chitotriosidase activity decreased from 6181 to 2877 nkat/L. Our observation and previous reports suggest that enzyme replacement therapy is more effective in polyclonal hypergammaglobulinaemia than in monoclonal gammopathy.

[Epidemiology of monoclonal gammopathy in a general hospital and a university internal medicine department]. / Epidémiologie descriptive des gammapathies monoclonales. Expérience d'un centre hospitalier général et d'un service de médecine interne de centre hospitalier et universitaire.

PURPOSE: Monoclonal gammopathy are common in the general population. We describe biological features and etiology of monoclonal gammopathy diagnosed during more than a ten year period in the Internal Medicine Department of Rennes University Hospital and in all the medical departments of General Hospital of Blois. METHODS: Patients were identified by immunofixation registry of Biochemistry Laboratories in both hospital (from 1990 in Rennes and from 1980 in Blois). RESULTS: Internal Medicine Department of Rennes University Hospital: 1051 monoclonal gammapathies were identified: 514 men and 537 women. Median age was 71. Isotypes repartition was: IgG 42.8% (450 cases), IgM 31.9% (335), IgA 8.9% (94) biclonal gammopathy 9.8% (103). Sixty-nine monoclonal light chains (6.6%) were identified. Median concentration of monoclonal protein was 14 g/l (1.8-104.4). All department of General Hospital of Blois: 1282 monoclonal gammapathies were identified: 700 men and 582 women. Median age was 79. Isotypes repartition was: IgG 59.7% (765 cases), IgM 27.5% (329), IgA 11.8% (151). Thirty-four monoclonal light chains (2.7%) were identified. Median concentration of monoclonal protein was 5.6 g/l (0.5-96.6). Most frequent diagnosis were: monoclonal gammopathy of undetermined significance or MGUS (77.6% in Blois and 64.1% in Rennes), multiple myeloma (11.9% and 12.7%), Waldenström's macroglobulinemia (4.4% and 8.7%). CONCLUSION: Monoclonal gammopathy are common in clinical practice. MGUS account for more than 60% of monoclonal gammopathy. Given their frequency, diagnostic and follow-up strategies must be costless and simple.

[Usefulness of a free light chain immunoassay in serum for the diagnosis and the follow-up of monoclonal gammopathy]. / Intérêt du dosage des chaînes légères libres d'immunoglobulines sériques pour le diagnostic et le suivi des gammapathies monoclonales.

PURPOSE: Monoclonal immunoglobulin free light chains (FLC) are present in the serum and urine of many patients with monoclonal gammopathies. In this review, we discuss the usefulness of serum FLC determination for diagnostic, prognostic and monitoring of multiple myeloma (MM), AL amyloidosis and monoclonal gammopathies of undetermined significance (MGUS). CURRENT KNOWLEDGE AND KEY POINTS: Serum FLC assay is a useful laboratory test for management of light chain MM, non-secretory MM and AL amyloidosis. Currently, serum FLC testing cannot be recommended for monitoring intact immunoglobulin multiple myeloma. Even though serum FLC determination give a better risk stratification for MGUS, systematic serum FLC assay should not be used in routine because of high MGUS occurrence in the general population. FUTURE PROSPECTS AND PROJECTS: Further prospective studies with large cohorts of patients should provide additional evidence for the role of serum FLC measurement in patients with intact immunoglobulin multiple myeloma.

[Efficiency of rituximab in acquired hemophilia: report of two cases and review of literature]. / Efficacité du rituximab dans les hémophilies acquises: à propos de deux cas et revue de la littérature.

INTRODUCTION: Acquired hemophilia due to an inhibitor of factor VIII is a rare clinical situation. EXEGESIS: Rituximab is now used in the treatment of acquired hemophilia. We report two cases of acquired hemophilia treated by rituximab with efficiency. CONCLUSION: Rituximab appears to be a first line immunosuppressive therapy in acquired hemophilia, especially in post-partum hemophilia.

[Diagnosis of solid malignancies in an internal medicine unit: a series of 114 consecutive cases]. / Le diagnostic des cancers solides dans un service de médecine interne: étude descriptive de 114 cas consécutifs.

PURPOSE: A deterioration of the general condition, a prolonged fever or an unexplained inflammatory syndrome are frequent reasons for hospitalization in a internal medicine unit. In these situations, it is not rare to make a diagnosis of cancer. PATIENTS AND METHODS: A descriptive study was carried out over a three years period (1st October 1999 to 30th September 2002) in an internal medicine unit. Every week, all patients in whom a cancer was diagnosed were enrolled in the study. RESULTS: During this period, 165 patients were identified (3.8% of the in-patients). A histological proof was obtained in 114 patients. Digestive and bronchopulmonary cancers were the most frequent. The first signs were very varied but digestive disorders and ferriprive anaemia were the most frequent. The number of investigations necessary to diagnosis were weak (1.56 procedures) when a sign was identified but were high (5.12 procedures) when no information was provided by interview, clinical examination or usual biological tests. CONCLUSION: Diagnosis of cancer is an usual situation in an internal medicine unit. Interview and clinical examination are essential in the diagnostic step. It could decrease the number of procedures. Internal unit services are fully concerned by the announcement of cancer.

[Thoracic infectious aortitis: microbiology, pathophysiology and treatment]. / Aortites thoraciques infectieuses: implications microbiologiques, physiopathologiques et thérapeutiques.

BACKGROUND: Thoracic infectious aortitis are currently rare. They are always lethal without any treatment. The microorganisms involved are numerous with particular pathophysiological characteristics for each bacterium. Treatment is difficult and must associate medical and surgical care. RECENT FINDINGS: Bacterial epidemiology of infectious aortitis has been profoundly modified with the large use of antibiotics. Syphilitic aortitis were frequent in the beginning of the twentieth century but its incidence has dramatically fallen. It still exists and its clinical presentation must be known to begin an adequate treatment. Other bacterial aetiologies of these aortitis are more classical with high frequencies of Staphylococcus aureus and Streptococcus, which are often associated with infective endocarditis. Among Gram-negative bacteria, Salmonella spp are the most frequently met microorganisms. Atherosclerosis represents the principal risk factor of these infectious aortitis. It provokes arterial parietal damage useful for bacterial attach. A saccular aneurysm of infective origin can then appear. Treatment must consist on antibiotics before surgery; Tuberculous aortitis are also possible but are much more rare. CONCLUSION: Thoracic infectious aortitis are very rare but must be known because of their poor prognosis. Treatment is difficult and prevention of atherosclerosis which is the most important risk factor of these diseases is therefore of greatest importance.

[Syphilitic aortitis. Experience of an internal medicine unit]. / Les aortites syphilitiques. Expérience d'un service de médecine interne.

INTRODUCTION: Infectious aortitis remains a rare disease. It is characterized by an endarteritis of infectious origin generally followed by the development of a so called mycotic aneurysm. Those infectious aneurysms account for 0.5 to 1.3% of all aortic aneurysms. Of the infectious agents, Treponema pallidum has a particular place. Cardiovascular syphilitic infection was very common at the beginning of the XX(th) century with a prevalence of 6.9% of all autopsies. In 1950-1960, the prevalence had decreased to less than 1%. Since 1990, syphilis was considered as disappeared. EXEGESIS: we report syphilitic aortitis in four patients. Diagnosis, treatment, and prognosis are detailed. CONCLUSION: A syphilitic infection of the aorta should be looked for in every patient suffering from an inflammatory or infectious disease of aorta.

[Cryptococcal infections in non-HIV infected patients. Study of four cases and review of literature]. / Infections à cryptocoque chez des patients non VIH. A propos de quatre cas et revue de la littérature.

BACKGROUND: Cryptococcal infections are frequent in HIV-infected patients and are regularly looked after. This infection may occur in others immunosuppressives situations and, in those cases, diagnosis is often delayed. METHODS: We report four cases of cryptococcal infections in patients whose immunosuppression isn't related with HIV infection but due to chronic lymphocytic leukemia, giant cell temporal arteritis, gastric neoplasm and lupus. Diagnosis, prognostic and treatment are detailed. RESULTS: Four patients aged from 25 to 76 presented a cryptococcal infection (three meningitis). A woman died at the admission. Another died seven years later. The two others are still alive under treatment. When infected, all patients were immunodeficiency. CONCLUSION: Cryptococcal infection may occur in patients non-HIV-infected patients. Early detection is needed to improve prognostic.

14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myélome.

Clonal plasma cells in monoclonal gammopathy of undetermined significance (MGUS) have been shown to bear copy number chromosome changes. To extend our knowledge of MGUS to structural chromosomal abnormalities, we have performed fluorescence in situ hybridization experiments with probes directed to the 14q32 and 13q14 chromosomal regions in 100 patients with either MGUS or smoldering multiple myeloma (SMM). 14q32 abnormalities were observed in at least 46% of patients with MGUS/SMM, with these abnormalities being present in the majority of clonal plasma cells. Whereas t(11;14)(q13;q32) occurs in 15% of MGUS/SMM patients, an incidence similar to that of overt multiple myeloma (MM) patients, translocation t(4;14)(p16;q32) is observed in only 2% of these cases [P = 0.002 for difference with t(11;14)], as compared with 12% in MM patients (P = 0.013). Monoallelic deletions of the 13q14 region were found in 21% of patients, with two types of situations. In half of the evaluable patients, and especially in patients with SMM, the deletion is present in the majority of clonal plasma cells, as in MM, whereas in the other half of the evaluable patients (essentially in MGUS patients), it is observed in subclones only. These data enable us to elaborate a plasma cell oncogenesis model from MGUS to MM.

Long-term outcome with pentostatin treatment in hairy cell leukemia patients. A French retrospective study of 238 patients.

With the introduction of new drugs such as alpha-interferon (IFN) and purine analogs, the management of hairy cell leukemia (HCL) patients has changed. However, deoxycoformycin (DCF) produced higher complete remission rates than IFN. The current study was undertaken to provide long-term data on duration of overall survival (OS) and disease-free survival (DFS) and incidence of subsequent malignancies. We retrospectively analyzed the data of patients treated with DCF (4 mg/m2/day, every 2 weeks) from 39 French centers. In 84 of 238 included patients, DCF was the first-line therapy. Pretreatment variables influencing the achievement of complete remission, DFS, and OS were identified by multivariate analysis. Two hundred and thirty-eight patients received a median of nine cycles (range, 1-19 cycles). A complete remission was obtained in 182 of 230 evaluable patients (79%) and a partial response was obtained in 38 patients, for an overall response rate of 95.6%. In the multivariate analysis hemoglobin level less than 100 g/l and leukocytes less than 2 x 10(9)/l were parameters adversely influencing complete remission achievement. With a median follow-up of 63.5 months (range, 0.39-138.4 months), disease recurrence was observed in 34 of 220 responding patients (15%). The estimated 5-years and 10-years DFS was 88.1% and 68.8%, respectively. Hemoglobin level less than 100 g/l and leukocytes less than 2 x 10(9)/l were the pre-treatment variables associated with a shorter DFS. The estimated 5-year and 10-year OS were 89.4% and 88.7%, respectively. Hemoglobin level less than 100 g/l, leukocytes less than 2 x 10(9)/l, and adenopathy were significant factors of reduced survival. Hematologic toxicity was the main side-effect, followed by infection and emesis. During the period of follow-up, 18 patients developed second cancer, but the standardized incidence ratio was 0.95. Pentostatin is a highly effective regimen for hairy cell leukemia that produces durable complete responses. Toxicity of DCF is acceptable. Subsequent malignancies do not appear to be increased with pentostatin treatment.

Mature plasma cells as indicator of better prognosis in multiple myeloma. New methodology for the assessment of plasma cell morphology.

The relationship between plasmablastic cells and outcome in multiple myeloma (MM) has been established for nearly 15 years. But the assessment of these cells is not easy to perform and it allows the identification of only a small proportion of patients. We investigated the plasma cell morphology using a progressive evaluation of consecutive criteria: nucleolus, chromatin and nuclear-cellular ratio (N/C). The combination of these three items produces a subclassification where four cellular subtypes identify 93% of the plasma cells, and these subtypes are related to the outcome. The interest of this methodology is to be based on the mature plasma cells that are easier to identify than the plasmablastic cells. These new cell subtypes introduce a new classification for patients: Group 1 includes patients with at least 66% mature plasma cells (P000). Both Group 2 and 3 have less than 66% P000 and are separated by their degree of maturation (Proplasma I > or = Proplasma II + plasmablastic). The distinction of these three groups of patients is highly related to the prognosis (P < 10(-4)). These results have been confirmed on a second group of patients coming from a different institution. In conclusion, we propose a new methodology for the plasma cell evaluation in MM, that is based on the morphological criteria and that has the advantage of identifying an intermediate (30%) subgroup of patients with a prognostic significance.

Thalidomide in patients with advanced multiple myeloma.

INTRODUCTION: Recently, a report has suggested the efficacy and safety of thalidomide in refractory multiple myeloma. In an attempt to assess the efficacy and tolerance of thalidomide in advanced multiple myeloma (on behalf of the Intergroupe Franchophone dy Myelome (IFM)), we report the preliminary experience of the IFM with this drug. MATERIALS AND METHODS: Patients with advanced multiple myeloma (n=27) were treated with an oral dose of thalidomide (median 400 mg/day). At the start of treatment, all patients had active disease and 20 patients had received at least one autologous transplantation. RESULTS: Median follow-up was 105 days from the first administration. The serum and/or urine levels of the M-component were reduced by at least 75% in four patients including one patient with a >90% reduction, by at least 50% in five patients and by at least 25% in three patients, giving a total response rate of 45% (12 out of 27 patients). Nine patients had stable disease and six patients had progressed disease. Short-term side-effects of thalidomide were generally moderate. CONCLUSION: This study confirms that thalidomide is an effective agent in patients with advanced myeloma.

Lack of efficacy of 2-chlorodeoxyadenoside in the treatment of splenic lymphoma with villous lymphocytes.

Splenic lymphoma with villous lymphocytes (SLVL) is a B-cell chronic lymphoproliferative disorder. Splenectomy and/or chlorambucil (CLB) are usually regarded as the most effective treatment in SLVL patients. However, a few patients relapse and the second line therapy remains questionable. Although 2-Cda has been evaluated in patients with chronic lymphoid leukemia (CLL) and hairy cell leukemia (HCL), it has been reported as the treatment of SLVL in only one case report. Therefore, we have evaluated its efficacy and toxicity in 7 SLVL patients. The median duration between diagnosis and treatment was 18 months (range, 1 to 59). The patients received 2-CdA (0.1 mg/kg/d) by venous infusion for 7 days with a median number of 1 cycle (range, 1 to 2) either as a first line therapy (one patient) or after a failure of other therapies (splenectomy, chemotherapy). Two patients achieved a complete response. The first one maintained his CR during a follow-up of 9 months and then relapsed; the second patient remained in CR after a follow-up of 20 months. Four patients achieved a partial response and relapsed after a median follow-up of 3.5 months (range, 1 to 4). One patient had no response. The treatment was not well tolerated with many infectious events. In the limits of our study, 2-Cda does not appear to be efficient therapy for SLVL and is not well tolerated for patients in relapse after splenectomy or resistant to CLB.

Multifactorial drug-resistance phenomenon in acute leukemias: impact of P170-MDR1, LRP56 protein, glutathione-transferases and metallothionein systems on clinical outcome.

The multidrug resistance phenomenon can be observed in cases which do not express the P170 protein and these cases are suspected as having activated different resistance phenomena. Four phenomena were studied at the time of diagnosis in a series of 35 lymphoblastic and 25 myeloblastic acute (de novo) leukemias, by an immunocytochemical method. Two energetic drug transport processes were investigated: the classical MDR/P170 and the P110/LRP56 proteins, and two physiological detoxifying activities such as the glutathione transferases (GST alpha, mu, pi) and the metallothioneins (Mts). The results demonstrate that these phenomena are independent but their synergic activity can increase their impact on the outcome. P110/LRP56 positive cases demonstrated 48.8% complete remission (CR) rate compared to 71.4% for negative tests. When P170 and P110 were both positive or negative, the CR rates were 27.3% and 81.8% respectively (p = 0.0120), and survival curves were also different (p = 0.030). The CR rate in AML or ALL is weakly affected by GST pi, alpha or mu but relapses are more frequently observed for Positive-GST pi ALL (p = 0.0658). Patients with both P170 and GST pi positive reactions had a 53.3% CR rate compared to 78.9% for both negative reactions. Survival curves for these two groups were different. The CR rate in AMl was 100% for Mts positive and 43.7% for negative cases (p = 0.050), however the median survival was totally different for these two groups (p = 0.046). CR rates were 26.6% for patients who were P170 positive and Mts negative compared to 100% for P170 negative and Mts positive (p = 0.038) patients. Survival curves were also different (p = 0.0510). We conclude that these four mechanisms induce an independent drug resistance but their synergic action increase their impact on the outcome. The metallothioneins seem to have a major impact on the drug resistance phenomenon and its effect should be investigated with high priority, in the light of these results.