Human herpesvirus 8+ polyclonal IgMλ B-cell lymphocytosis mimicking plasmablastic leukemia/lymphoma in HIV-infected patients.

PURPOSE: Multicentric Castleman disease (MCD) is a distinct lymphoproliferative disorder characterized by inflammatory symptoms, lymphadenopathy, splenomegaly, and cytopenia. Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8), is the cause of virtually all cases of MCD occurring in patients with HIV infection. MCD lesions characteristically contain HHV-8-infected polyclonal IgMλ plasmablasts. A high frequency of HHV-8-related non-Hodgkin lymphoma has been reported in these patients. PATIENTS AND METHODS: We now report on three patients who presented with severe symptoms of MCD, extreme splenomegaly, and rapid expansion of B-cell lymphocytosis (44-81%) attributable to circulating HHV-8 positive plasmablasts. RESULTS: The circulating plasmablastic cells shared the phenotype (IgMλ, CD19+, CD20- CD138-) of HHV-8-infected cells from MCD lesions, mimicking the leukemic phase of large B-cell lymphoma occurring in HHV-8-related MCD. These patients displayed a very high HHV-8 viral load in blood (>7 logs HHV-8 DNA copies/ml) and high levels of serum vIL-6, the viral homolog of human interleukin 6. Serum IL-6 and IL-10 were also abnormally elevated. HHV-8-infected cells were demonstrated by immunoglobulin gene rearrangement analysis, to be polyclonal and likely represent an expansion of HHV-8-infected cells similar to those found in MCD lesions. CONCLUSION: Thus, the spectrum of HHV-8-related plasmablastic lymphoproliferative disorders in patients with HIV infection is expanded to include HHV-8+ polyclonal IgMλ B-cell lymphocytosis. At onset, this lymphoproliferative disorder may mimic plasmablastic leukemia/lymphoma. Recognizing this unusual complication may have important implications in treatment decision avoiding unnecessary toxicity to the patients.

Adverse prognostic significance of CD20 expression in adults with Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia.

The prognostic significance of CD20 expression in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been mostly studied in children and yielded conflicting results. In 143 adults with Philadelphia chromosome-negative BCP-ALL treated in the multicentric GRAALL 2003 trial, CD20 positivity over 20% was observed in 32% of patients. While not influencing complete remission achievement, CD20 expression was associated with a higher cumulative incidence of relapse (CIR) at 42 months (P=0.04), independently of the ALL high-risk subset (P=0.025). Notably, the negative impact of CD20 expression on CIR was only observed in patients with a white blood cell count (WBC) over 30x10(9)/L (P=0.006), while not in those with a lower WBC. In the former subgroup, this impact translated into lower event-free survival (15% vs. 59% at 42 months, P=0.003). CD20 expression thus appears to be associated with a worse outcome, which reinforces the interest of evaluating rituximab combined to chemotherapy in CD20-positive adult BCP-ALL. ClinicalTrials.gov ID, NCT00222027.

A paraneoplastic membranoproliferative glomerulonephritis with isolated C3 deposits associated with hairy cell leukaemia.

We describe a 35-year-old woman who presented with proteinuria and microscopic haematuria. Blood tests revealed a low C3 complement level, with no evidence of cryoglobulin. Renal biopsy showed a Type 1 membranoproliferative glomerulonephritis (MPGN) with isolated C3 deposits on immunofluorescence study. Bone marrow aspirate, done for monocytopenia, was consistent with a diagnosis of hairy cell leukaemia (HCL). Both haematological and nephrological diseases completely responded to treatment with cladribine, strongly suggesting that the renal disease was a paraneoplastic syndrome. To our knowledge, this is the first report of a non-cryoglobulinaemic MPGN associated to HCL.

Mutual benefits of B-ALL and HLDA/HCDM HLDA 9th Barcelona 2010.

The B-cell panel of the ninth HLDA was applied in a multicentre fashion to cryopreserved cells from 46 patients with acute lymphoblastic leukemia. The reagents were aliquoted and shipped to volunteer participants from the French Groupe d'Etude Immunologique des Leucémies (GEIL). All samples were tested in flow cytometry, and the results collected as of the strength of labeling of the leukemic clone as negative, weak or strong. Among the 64 antibodies tested, the strongest and most frequent staining was observed for CD305 (LAIR), CD229 (Ly9), CD200 (OX-2) and, to a lesser extent, CD361 (EVI2b). Details of the observations, and information about the molecules tested are provided in the manuscript as well as a summary table.

Critical care management of patients with hemophagocytic lymphohistiocytosis.

OBJECTIVE: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition associated with multiple organ dysfunction. We sought to describe ICU management and outcomes in HLH patients meeting HLH-2004 criteria and to identify determinants of mortality. DESIGN: Retrospective study between January 1998 and January 2009. SETTING: Medical ICU of a teaching hospital. PATIENTS: Among the 72 patients fulfilling the HLH-2004 criteria, we report the 56 patients with complete follow-up and no missing data. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical and laboratory data were abstracted from the medical records. Median SOFA score at admission was 6.5 (IQR, 4-8). At ICU admission, the number of HLH-2004 criteria was 6 (5-7). Sixty-six precipitating factors were found in 52 patients and consisted of 43 tumoral causes (8 Castleman's diseases, 18 B cell lymphoma and 17 various malignancies), 13 non-viral infections and 10 viral infections. Underlying immune deficiency was present in 38 (67.8%) patients. Etoposide was used in 45 patients, corticosteroids in 31 and intravenous immunoglobulins in 3. Mechanical ventilation was required in 32 patients, vasoactive agents in 30 and renal replacement therapy in 19. Hospital mortality was 29/56 patients. By multivariate analysis, factors associated with increased hospital death were shock at ICU admission [OR, 4.33; 95% confidence interval (95% CI), 1.11-16.90; P = 0.03] and platelet count <30 g/l (OR, 4.75; 95% CI, 1.20-18.81; P = 0.02). B cell lymphoma [odds ratio (OR), 0.17; 95% CI, 0.04-0.80; P = 0.02] and Castleman's disease (OR, 0.11; 95% CI, 0.02-0.90; P = 0.04) were associated with increased hospital survival. CONCLUSIONS: Aggressive supportive care combined with specific treatment of the precipitating factor can produce meaningful survival in patients with HLH responsible for multiple organ failures. Survival is highest in patients with HLH related to Castleman's disease or B cell lymphoma.

Reactive haemophagocytic syndrome in 58 HIV-1-infected patients: clinical features, underlying diseases and prognosis.

OBJECTIVE: To describe features of reactive haemophagocytic syndrome (RHS) in HIV-1-infected adult patients. To compare characteristics of patients with malignancy-associated RHS and infection-associated RHS. DESIGN AND SETTING: Retrospective study in three departments of Infectious Diseases/Internal Medicine at three French tertiary centres. PATIENTS AND METHODS: Medical charts of HIV-1-infected adult patients and RHS seen between January 2006 and December 2007 were reviewed. Demographic, clinical and laboratory data obtained at the time of RHS episode were compared between patients with malignancy-associated RHS and infection-associated RHS using non-parametric tests. The overall survival was assessed using the Kaplan-Meier method. RESULTS: Fifty-eight HIV-1-infected patients were diagnosed with RHS [certain RHS n = 43, possible RHS n = 15, median (range) age 42 (23-85) years, men 76%]. At time of RHS, the median duration of HIV infection was 4 (0-22) years and 57% received HAART. The median CD4 lymphocyte count was 91 (2-387)/microl and 35% of patients had a plasma HIV-1 RNA less than 50 copies/ml. Underlying haemopathy/malignancy (Hodgkin lymphoma n = 10) or infection (tuberculosis n = 9, cytomegalovirus infection n = 5) were evidenced for 31 and 23 patients, respectively. Patients with haemopathy/malignancy-associated RHS presented more frequently with splenomegaly (97 vs. 70%, P < 0.01), lower aspartate aminotransferase (36 vs. 84 UI/l, P < 0.01) and lactate dehydrogenase (530 vs. 911 UI/l, P < 0.01) levels and CD8 cell count (234 vs. 588/microl, P < 0.01). Eighteen (31%) patients died. The overall survival was not statistically different between the two groups (P = 0.68). CONCLUSION: In the HAART era, RHS is frequently associated with underlying haemopathy/malignancy, especially Hodgkin lymphoma. The prognosis remains poor but seems, however, better than in the pre-HAART era.

Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome.

In this Phase 2 study, we evaluated the efficacy of combination of 5-azacitidine (AZA), valproic acid (VPA), and all-trans retinoic acid (ATRA) in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Treatment consisted of six cycles of AZA and VPA for 7 days, followed by ATRA for 21 days. Sixty-five patients were enrolled (median age, 72 years; 55 AML including 13 relapsed/refractory patients, 10 MDS; 30 unfavorable karyotypes). Best responses included 14 CR and 3 PR (26%), 75% of the responders and 36% of the non-responders achieving an erythroid response. Median overall survival (OS) was 12.4 months. Untreated patients had a longer OS than relapsed/refractory patients. In patients who fulfilled the 6 planned cycles, OS did not appear to depend on CR/PR achievement, suggesting that stable disease while on-treatment would be a surrogate for survival with this approach. During therapy, early platelet response and demethylation of the FZD9, ALOX12, HPN, and CALCA genes were associated with clinical response. Finally, there was no evidence for the restoration of an ATRA-induced differentiation during therapy. Epigenetic modulation deserves prospective comparisons to conventional care in patients with high-risk AML, at least in those presenting previously untreated disease and low blast count.

Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study.

The combination of imatinib with chemotherapy has been recently reported as very promising in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). During 2004 and 2005, 45 patients with newly diagnosed Ph+ ALL were treated in the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAAPH) 2003 study, in which imatinib was started with HAM (mitoxantrone with intermediate-dose cytarabine) consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders (corticoresistant and/or chemoresistant ALL). Imatinib was then continuously administered until stem cell transplantation (SCT). Overall, complete remission (CR) and BCR-ABL real-time quantitative polymerase chain reaction (RQ-PCR) negativity rates were 96% and 29%, respectively. All of the 22 CR patients (100%) with a donor actually received allogeneic SCT in first CR. At 18 months, the estimated cumulative incidence of relapse, disease-free survival, and overall survival were 30%, 51%, and 65%, respectively. These 3 end points compared very favorably with results obtained in the pre-imatinib LALA-94 trial. This study confirms the value of the combined approach and encourages prospective trials to define the optimal chemotherapy that has to be combined with imatinib and to carefully reevaluate the place of allogeneic SCT in this new context.