First-line imatinib mesylate in patients with newly diagnosed accelerated phase-chronic myeloid leukemia.

Imatinib mesylate is the sole BCR-ABL tyrosine kinase inhibitor approved as first-line treatment of accelerated-phase (AP) chronic myeloid leukemia (CML). Indication was based on the STI571 0109 study, in which imatinib favorably compared to historical treatments in patients failing prior therapies. The relevance of these results to currently newly diagnosed AP-CML patients remains unknown. We evaluated the benefit of imatinib in 42 newly diagnosed AP-CML patients. In all, 16 patients had hematological acceleration without chromosomal abnormalities in addition to the Philadelphia chromosome (ACAs; HEM-AP), 16 solely had ACAs (ACA-AP) and 10 had hematological acceleration plus ACAs (HEM-AP + ACA). Major cytogenetic responses were achieved in 93.7% of HEM-AP patients, 75% of patients with ACA-AP (P=NS) and 40% of patients with HEM-AP + ACA (P=0.0053). The 24-month failure-free survival rate was 87.5% in HEM-AP patients, 43.8% in ACA-AP patients and 15% in HEM-AP + ACA patients (P=0.022). The 24-month estimate of progression-free survival was 100% in HEM-AP patients, 92.8% in ACA-AP patients and 58.3% in HEM-AP + ACA patients (P=0.0052). In conclusion, frontline imatinib allows favorable outcomes in HEM-AP and ACA-AP patients but appears insufficient for patients with HEM-AP + ACA. Broader-target and/or more potent BCR-ABL tyrosine kinase inhibitors alone or in combination may be considered in this setting.

[Guidelines for the management of nilotinib (Tasigna)-induced side effects in chronic myelogenous leukemia: recommendations of French Intergroup of CML (Fi-LMC group)]. / Recommandations du groupe Fi-LMC pour la gestion des effets indésirables du traitement par nilotinib (Tasigna) au cours de la leucémie myéloïde chronique.

Nilotinib (Tasigna) is a second-generation BCR-ABL kinase inhibitor, recently introduced and used for the treatment of chronic or accelerated phase CML patients, intolerant or resistant to imatinib. This treatment represents and important step forward for the disease control of such patients but can lead to side effects, sometimes serious, which can limit its optimal use. We propose here some guidelines that might be of help in daily practice, in order to manage properly these side effects.

[Eosinophilic pleural effusion associated to Churg and Strauss syndrome]. / Epanchement pleural éosinophile associé à un syndrome de Churg et Strauss.

Eosinophilic pleural effusion (EPE) is defined as pleural eosinophilia greater than 10%. EPE can be seen in almost all conditions that can cause pleural effusion, but some aetiologies have to be investigated due to their frequency or potential severity. The most common aetiology of EPE is the presence of air or blood in the pleural cavity. Other frequent aetiologies include bacterial pneumonia, tuberculosis, parasitic disease and certain drugs. Although often considered to be a sign of a benign condition, pleural eosinophilia may be associated with malignancies. EPE may also indicate the presence of Churg and Strauss syndrome. We report the case of a 27-year-old man, in whom the exploration of EPE led to the diagnosis of Churg and Strauss syndrome with the association of asthma, blood and alveolar eosinophilia, myopericarditis and positive antineutrophil cytoplasmic antibodies (ANCA). This case report enables us to discuss the different causes of EPE and to illustrate how it may be a manifestation of Churg and Strauss syndrome.

Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP).

The emergence of ABL point mutations is the most frequent cause for imatinib resistance in chronic myelogenous leukemia (CML) patients and can occur during any phase of the disease; however, their clinical impact remains controversial. In this study, we retrospectively analyzed the predictive impact of 94 BCR-ABL kinase domain mutations (18 T315I, 26 P-loop, 50 in other sites) found in 89 imatinib-resistant CML patients. At imatinib onset, 64% of patients (57/89) were in chronic phase (CP), 24% (21/89) in accelerated phase (AP) and 12% (11/89) in blastic phase (BP). T315I and P-loop mutations were preferentially discovered in accelerated phase of BP CML, and other types of mutations in CP (P=0.003). With a median follow-up of 39.2 months (6.3-67.2), since imatinib initiation, overall survival (OS) was significantly worse for P-loop (28.3 months) and for T315I (12.6 months), and not reached for other mutations (P=0.0004). For CP only, multivariate analysis demonstrated a worse OS for P-loop mutations (P=0.014), and a worse progression-free survival (PFS) for T315I mutations (P=0.014). Therefore, P-loop and T315I mutations selectively impair the outcome of imatinib-resistant CML patients, in contrast to other mutations, which may benefit from dose escalation of imatinib, able to improve or stabilize disease response.

Response to antiviral treatment in hepatitis C virus-associated marginal zone lymphomas.

A link between chronic hepatitis C virus (HCV) infection and low-grade B-cell lymphomas has been suggested by epidemiological studies. Marginal zone lymphomas (MZLs) including splenic lymphomas with villous lymphocytes are among the most frequently reported subgroups in the setting of chronic HCV infection. In this study, we examined the effect of antiviral treatment in eight patients with HCV-associated MZL. We found that five out of eight patients have responded to interferon alpha and ribavirin. In some cases, hematologic responses were correlated to virologic responses. In addition, we report a case of large granular lymphocyte leukemia occurring in association with MZL and HCV, and responding to interferon and ribavirin. We suggest that there is an etiologic link between HCV and antigen-driven lymphoproliferative disorders.

[Epstein-Barr virus-associated cutaneous plasmacytoma post-solid organ transplantation]. / Plasmocytomes cutanés associés au virus Epstein-Barr chez les transplantés d'organes.

BACKGROUND: Post-transplantation lymphoproliferative disorders develop in 1 to 10p. 100 of organ transplant recipients and are frequently associated with Epstein-Barr virus (EBV). Among post-transplantation lymphoproliferative disorders, plasmacytoma with cutaneous involvement is exceptional. Association with EBV has been rarely reported in post-transplantation plasmacytomas and the latency type of EBV has never been characterized. We report 2 new cases of cutaneous monotype EBV-related plasmacytomas. CASE-REPORTS: Clinical presentation was a sub-cutaneous tumor on the thigh in the first case and an ulcerated nodule of the leg in the second case, occurring respectively 7 and 8 years after organ transplantation (liver transplantation and heart transplantation). In both lesions, tumor cells exhibited lambda light chain restriction and the association with EBV was confirmed using immunohistochemistry and in situ hybridization. The expression of EBV genes in tumor cells demonstrated type III latency. DISCUSSION: The classification of post-transplantation lymphoproliferative disorders is not well defined and some authors retain 3 categories. Among the latter, plasmacytomas have been rarely described. Cutaneous involvement is reported in 4 cases and an association with EBV in only 2 cases without description of viral latency. Clinical and histological features of post-transplantation plasmacytomas appear polymorphic. We report EBV-association in both cases, with a type III latency clearly demonstrated in one case, as has been reported in other lymphoproliferative diseases in patients with congenital or acquired immunodeficiency. We also discuss various possible therapeutic strategies for post-transplantation lymphoproliferative disorders.

The superoxide dismutase mimetic MnTBAP prevents Fas-induced acute liver failure in the mouse.

BACKGROUND & AIMS: Acute liver failure (ALF) of viral origin results from massive hepatocyte apoptosis induced by the interaction between Fas expressed on hepatocytes and Fas ligand on activated T lymphocytes. Because Fas-induced apoptosis of hepatocytes involves mitochondrial damages and potential reactive oxygen species (ROS) overproduction, we investigated whether manganese III tetrakis (5,10,15,20 benzoic acid) (MnTBAP), a nonpeptidyl mimic of superoxide dismutase (SOD), can inhibit Fas-induced ALF. METHODS: An agonist anti-Fas monoclonal antibody was used to induce hepatocyte apoptosis in vitro and ALF in vivo. RESULTS: Preventive and curative treatments by MnTBAP significantly increased survival rates and significantly reduced aspartate aminotransferase levels and parenchymal lesions. ROS generation was suggested by those beneficial effects and significant increases in SOD and Gpx activities after anti-Fas injection. Flow cytometry of isolated hepatocytes incubated with anti-Fas monoclonal antibody showed that ROS production was associated with the collapse of transmembrane potential and loss of cardiolipin content. After injection of anti-Fas monoclonal antibody, mitochondrial Bcl-2 was decreased, cytochrome c released, and caspase-3 activated. Mitochondrial alterations and their consequences were abrogated by MnTBAP. CONCLUSIONS: ROS are key executioners in Fas-induced hepatocyte apoptosis. This finding explains why a nonpeptidyl mimic of SOD can cure ALF in a model of viral hepatitis, pointing out the potential interest of this molecule in humans.

Human immunodeficiency virus-related lymphoma: relation between clinical features and histologic subtypes.

PURPOSE: Non-Hodgkin's lymphoma occurs frequently in patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). We determined the association between the clinical and histologic features of HIV-related lymphoma. SUBJECTS AND METHODS: We reviewed the medical records of 291 patients with noncerebral HIV-related lymphoma who had been treated in multicenter trials coordinated by the Groupe d'Etude des Lymphomes de l'Adulte between 1988 and 1997. This study was performed mainly before the availability of combination antiretroviral therapy. RESULTS: The main histologic subtypes were centroblastic lymphoma in 131 patients (45%), immunoblastic lymphoma in 39 patients (13%), and Burkitt's lymphoma (including the classical form and the variant with plasmacytic differentiation) in 115 patients (40%). Burkitt's lymphoma was the most aggressive form, whereas immunoblastic lymphoma occurred in severely immunodeficient patients. Two-year survival after enrollment was 15% in immunoblastic lymphoma, 32% in Burkitt's lymphoma, and 31% in centroblastic lymphoma (P = 0.006), but multivariate analysis did not confirm the independent prognostic value of histologic subtype. Instead, five independent pretreatment factors increased the risk of mortality: age 40 years or older [relative risk (RR) = 1.5; 95% confidence interval (CI), 1.1 to 2.1; P = 0.005], elevated serum lactate dehydrogenase level (RR = 1.5; 95% CI, 1.1 to 2.1; P = 0.02), having a diagnosis of AIDS before lymphoma (RR = 1.8; 95% CI, 1.2 to 2.6; P = 0.006), CD4(+) cell count less than 100 x 10(6)/L (RR = 1.8; 95% CI, 1.3 to 2.6; P = 0.0004), and impaired performance status (RR = 2.4; 95% CI, 1.7 to 3.4; P <0.0001). CONCLUSION: Several pretreatment characteristics of HIV-related lymphoma were linked to the histologic form, but HIV disease parameters other than those of lymphoma were the main determinants of outcome, so the histologic features of the lymphoma were not associated with prognosis.

Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy.

HIV infection is associated with a high incidence of AIDS-related lymphomas (ARLs). Since the use of highly active antiretroviral therapy (HAART), the incidence of AIDS-defining illnesses has decreased, leading to a significant improvement in survival of HIV-infected patients. The consequences of HAART use on ARL are under debate. This study compared the incidence and the characteristics of ARL before and after the use of HAART in a large population of HIV-infected patients in the French Hospital Database on HIV (FHDH) and particularly in 3 centers including 145 patients with proven lymphoma. Within the FHDH, the incidence of systemic ARL has decreased between 1993-1994 and 1997-1998, from 86.0 per 10 000 to 42.9 per 10 000 person-years (P < 10(-30)). The incidence of primary brain lymphoma has also fallen dramatically between the periods, from 27.8 per 10 000 to 9.7 per 10 000 person-years (P < 10(-11)). The analysis of 145 cases of ARL in 3 hospitals showed that known HIV history was longer in the second period than in the first period among patients with systemic ARL (98 versus 75 months; P <.01). Patients had a higher number of CD4 cells at diagnosis during the second period (191 versus 63/microL, P = 10(-3)). Survival of patients with systemic ARL also increased between the periods (from 6 to 20 months; P =.004). Therefore, the profile of ARL has changed since the era of HAART, with a lower incidence of systemic and brain ARL. The prognosis of systemic ARL has improved.

Germ-line deletion of p53 reveals a multistage tumor progression in spi-1/PU.1 transgenic proerythroblasts.

Activation of the spi-1/PU.1 proto-oncogene and loss of p53 function are genetic alterations associated with the emergence of Friend malignant erythroleukemic cells. To address the role of p53 during erythroleukemogenesis, spi-1 transgenic mice (spi-1-Tg) which develop erythroleukemia were bred with p53-deficient mice. Three classes of spi-1 transgenic mice differing in their p53 functional status (p53(+/+), p53(+/-) and p53(-/-)) were generated. These mice developed a unique pattern of erythroleukemia. In wild-type p53 spi-1-Tg mice, none of the primary erythroleukemic spleen cells displayed autonomous growth in vitro and in vivo. In contrast, in p53(+/-) spi-1-Tg mice, erythroleukemic cells gave rise to growth factor-independent cell lines and generated tumors in vivo. Malignancy was associated with loss of the wild-type p53 allele. The p53(-/-) spi-1-Tg mice developed erythroleukemia with a total incidence and a reduced latency compared to the two other genotypes. Unexpectedly, 50% of p53(-/-) spi-1-Tg erythroleukemic spleens generated cell lines that were strictly dependent upon erythropoietin (Epo) for proliferation, whereas the remainder proliferated independently of cytokines. Moreover, only 70% of these spleen cells were tumorigenic. These findings indicate that p53 germ-line deletion did not confer malignancy to spi-1-transgenic proerythroblasts. Moreover Epo independence and tumorigenicity appear as separable phenotypic characteristics revealing that the spi-1-Tg proerythroblasts progress towards malignancy through multiple oncogenic events.

Detoxification of reactive oxygen species by a nonpeptidyl mimic of superoxide dismutase cures acetaminophen-induced acute liver failure in the mouse.

Drug-induced acute liver failure (ALF) is a devastating and often fatal disease mainly caused by poisoning by acetaminophen (APAP). The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), that leads to gluthatione depletion has been suspected to be the main effector of hepatocyte apoptosis during APAP-induced ALF. We have investigated whether reactive oxygen species (ROS) also play a role in APAP-induced ALF, and whether manganese III tetrakis (5,10,15,20 benzoic acid) (MnTBAP), a mimic of superoxide dismutase (SOD) with catalase-like activity, can treat the disease in mice. The effects of MnTBAP were tested on APAP-intoxicated mice and on isolated hepatocytes incubated with APAP. MnTBAP preventively and curatively administered significantly improved survival times, and dramatically reduced serum transaminase activity levels and parenchymal lesions in APAP-intoxicated mice. Whereas pretreatment with N-acetyl-L-cysteine (NAC) prevented ALF in a dose-dependent manner, the molecule was ineffective when curatively administered. The significant increase in glutathione peroxidase (Gpx) activity following APAP administration, and the beneficial effects of MnTBAP suggested that ROS were produced during APAP-induced ALF. A direct evidence of ROS generation was provided by flow cytometry of isolated hepatocytes incubated with APAP. In vitro, ROS production was associated with mitochondrial damage characterized by the collapse of transmembrane potential and the loss of cardiolipin content. In livers of intoxicated mice, ALF was associated with cytochrome c release that led to the activation of caspases-9 and -3. The capacity of MnTBAP to abrogate all those alterations suggests that ROS play a role in APAP-induced apoptosis of hepatocytes, and explains the beneficial effects of MnTBAP, which could be of interest in APAP-induced ALF in humans.

Chimerism analysis by lineage-specific fluorescent polymerase chain reaction in secondary graft failure after allogeneic stem cell transplantation.

BACKGROUND: Chimerism analysis is essential in understanding the etiology of graft failure occurring after allogeneic stem cell transplantation. The detection of marrow and/or blood host cells suggests graft rejection, relapse of the underlying disease, or a state of stable mixed chimerism. However, complete donor chimerism may be observed in some cases. Our objective was to characterize, by a sensitive process of chimerism analysis, six cases of graft failure occurring after transplant. METHODS: Six cases of secondary graft failure, in which previous analysis had shown complete donor chimerism by standard polymerase chain reaction amplification of variable number of tandem repeats, were studied. In order to detect a minority population of recipient cells, we increased the sensitivity of the process by using fluorescent polymerase chain reaction and analyzing the origin of T, B, and natural killer lymphocytes at the time of graft failure. RESULTS: The complete donor origin of mononuclear cells and lymphocytic populations was confirmed with this method in five of six patients. In the remaining patient, diagnosis of graft failure was clarified by the detection of a previously undetected mixed chimerism, compatible with graft rejection. In the other five patients, graft rejection was thereby excluded and graft failure could be related to viral infection or to graft-versus-host disease. CONCLUSION: Our sensitive process of fluorescent lineage-specific chimerism analysis may help in distinguishing between graft rejection and other mechanisms of graft failure, which is essential for deciding appropriate therapy.

Molecular epidemiology of human herpesvirus 8 in africa: both B and A5 K1 genotypes, as well as the M and P genotypes of K14.1/K15 loci, are frequent and widespread.

We have studied 52 new HHV8 strains by sequencing the complete hypervariable K1 gene and genotyping the K14.1/K15 loci located at both sides, respectively, of the viral genome. The samples originated from 49 patients with Kaposi's sarcoma (KS; 32 patients), multicentric Castleman's disease (MCD; 12 patients), or primary effusion lymphoma (PEL; 5 patients). Among these patients, 32 were of African origin (West and Central African countries and Creoles from French Guiana) and the 17 others were mostly French homosexuals. Comprehensive phylogenetic studies allowed the identification of distinct groups within the three already known main subtypes. Interestingly, two new sequences that did not cluster within a known subtype or group could be considered as prototypes of early/ancient variants of the C subtype and A/C set, respectively. Among the 32 African strains, the majority were either of the B subtype (13 cases) or of the A5 group (11 cases), indicating that this latter genotype is frequent and widespread in Africa. In contrast, a subtype C strain infected most of the 17 other patients. PCR-based genotyping of the K14.1/K15 loci revealed an overall predominance of P subtype, except in the A5 and B K1 groups, in which the P and M alleles were equally represented. The implications of these data on the evolution and spread of HHV8 among human African populations are discussed.

Monoclonality or oligoclonality of human herpesvirus 8 terminal repeat sequences in Kaposi's sarcoma and other diseases.

BACKGROUND: Infection with human herpesvirus 8 (HHV8), also termed Kaposi's sarcoma (KS)-associated herpesvirus, is associated with all forms of KS, with primary effusion lymphoma (PEL), and with some forms of multicentric Castleman's disease (MCD), but the pathogenic role of HHV8 in these tumors and the clonal nature of KS are still unclear. The purpose of this study was to examine whether the number of terminal repeats (TRs) contained in the fused TR region of HHV8 could be used as a marker of clonality in HHV8-associated tumors. METHODS: Pulsed-field gel electrophoresis (PFGE) and multiple-probe Southern blot analysis of the HHV8 TR region were performed on high-molecular-weight DNA obtained from tumoral KS, PEL, and MCD lesions. RESULTS: These analysis showed that the fused TR region contains a large but variable number of TR units (ranging from 16 to 75) and that the viral genome is present as extrachromosomal circular DNA in these tumors in vivo, with occasional ladders of heterogeneous linear termini reflecting lytic replication. All PEL tumors and PEL-derived cell lines as well as some KS tumors contained monoclonal or oligoclonal fused TR fragments; however, the TR region appeared polyclonal in MCD tumors and in a few KS lesions. CONCLUSION: Several KS and PEL lesions are monoclonal expansions of a single infected cell, suggesting that HHV8 infection precedes tumor growth and thus supporting an etiologic role of latent HHV8 in these proliferations. Our finding that nodular KS lesions display all possible patterns of clonality supports the model according to which KS begins as a polyclonal disease with subsequent evolution to a monoclonal process.

Methylenetetrahydrofolate reductase deficiency in four siblings: a clinical, biochemical, and molecular study of the family.

A diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency was made in four sibs at different ages. The first three, including a pair of twins, had retarded psychomotor development, poor social contact, and seizures. Biologically, hyperhomocysteinemia and hypomethioninemia were found associated with low folate levels in serum and red cells, especially undetectable methyltetrahydrofolate in red cells. In the fourth child, prenatal diagnosis was not conclusive because of moderate decrease of enzymatic activity in chorionic villi and trophoblast. The girl was also affected, as shown by hyperhomocysteinemia and low folate levels found several days after birth. A 677C-->T (Ala-->Val) mutation was found in a homozygous state in the four children and in the father. Additionally, a second homozygous mutation, 1081C-->T, changing an arginine to cysteine also was identified in all of the children, whereas the distantly consanguineous parents were heterozygous. This amino acid substitution affecting an arginine residue in a sequence located at the end of catalytic domain seems critical for the function of the enzyme. The difficulty of prenatal diagnosis is discussed given the variability found in enzymatic activity and in the clinical phenotypes.

Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with clonal lymphoproliferative disorders after orthotopic liver transplantation: a report of three cases.

BACKGROUND/AIMS: Post-transplant lymphoproliferative disorders (PT-LPD) are a well-known complication of organ transplantation. Their incidence after liver transplantation in adults ranges from 1.8 to 4%. Reduction of immunosuppression led to remission in a few cases. Other treatments include chemotherapy, interferon alpha therapy and/or intravenous-immunoglobulins, or antiviral drugs. However, monoclonal antibodies directed against B-cell specific antigens have rarely been used in those patients. Our aim was to study the feasibility and efficacy of Rituximab, a new, promising human chimeric antibody that recognizes the CD20 antigen, for the treatment of patients with clonal lymphoproliferative disorders after orthotopic liver transplantation. METHODS: Rituximab (IDEC-C2HB8; Roche Laboratories, Neuilly-sur-Seine, France) was administered at a 375 mg/m2 dose on days 1, 8, 15, and 22, in an outpatient setting, in three patients with PT-LPD. The tumor was classified as polymorphic PT-LPD in two cases and PT-LPD with features of large cell lymphoma in one case. All the tumors expressed the CD20 antigen and were EBV-related, and the clonality was confirmed in all three cases. The 4 injections of the anti-CD20 monoclonal antibody were associated with reduced immunosuppression in the three patient. RESULTS: The treatment with Rituximab was well tolerated without any side effects. The two patients with polymorphic PT-LPDs underwent rapid complete remission, whereas the treatment modalities were ineffective in the patient with the large-cell non-Hodgkin-lymphoma. CONCLUSION: These results must be confirmed in a larger cohort of liver transplant recipients suffering from lymphoproliferation. However, they indicate rapid efficiency of Rituximab in association with reduced immunosuppression in these disorders.