M. Christina Cox

Absolute lymphocyte count is a prognostic factor in diffuse large B-cell lymphoma

imab is associated with a reduction in IgG antibodies to ADAMTS13. British Journal of Haematology, 136, 451–461. Yarranton, H., Lawrie, A.S., MacKie, I.J., Pinkoski, L., Corash, L. & Machin, S.J. (2005) Coagulation factor levels in cryosupernatant prepared from plasma treated with amotosalen hydrochloride (S-59) and ultraviolet A light. Transfusion, 45, 1453–1458.

Chromosomal Aberration of the 11q23 Locus in Acute Leukemia and Frequency of MLL Gene Translocation Results in 378 Adult Patients

Structural abnormality of the 11q23 band (11q23+) bearing the MLL gene translocation (MLL+) is a recurrent chromosome change observed in 3% to 7% of acute lymphoblastic leukemias and in 3% to 4% of acute myeloblastic leukemias. The resolution of conventional cytogenetics (CC) in detecting 11q23 rearrangement is limited when the translocative partner has a telomeric location; furthermore, CC can barely discriminate between true 11q23+/MLL+ and rearrangements clustering within the 11q22~25 region without MLL involvement (MLL–). We characterized a series of 378 consecutive patients with adult acute leukemia by using CC, fluorescence in situ hybridization (FISH), and multiplex karyotyping (MFISH) analysis. Our aim was to define the frequency of cryptic MLL+ cases and the frequency of MLL+ within 11q22~25+ cases. As expected, FISH was more sensitive than CC in detecting MLL+ cases, but rather unexpectedly, 9 (45%) of 20 patients with 11q22~25+ were MLL–. A better characterization of 11q22~25+/MLL– leukemias is relevant for the identification of new, recurrent translocations. Moreover, these cases should be readily distinguishable from 11q23+/MLL+ cases. We recommend that karyotypic analysis always be complemented by molecular or FISH methods to unravel MLL rearrangements.

HCV-positive status and hepatitis flares in patients with B-cell non-Hodgkin's lymphoma treated with rituximab-containing regimens.

BACKGROUND Rituximab has provided a revolutionary contribution to the treatment of B-cell non-Hodgkins lymphomas (NHL). A high prevalence of hepatitis C virus (HCV) infection has been described in B-cell NHL patients. Cases of liver dysfunction in HCV-positive patients have been reported with rituximab-containing regimens. AIM to evaluate the liver-related effects of rituximab-containing regimens on HCV-positive CD20-positive B-cell NHL patients. PATIENTS AND METHODS Retrospective analysis of 104 consecutive patients. HCV status was determined, and development of hepatitis flares analysed. RESULTS Nine patients (8.6%) were HCV-positive. No correlation was shown between viral load and alanine transaminase levels. Three of the 9 HCV-positive, and none of the 95 HCV-negative developed hepatitis flares (p<0.001). At the 12-month follow-up hepatitis flare patients were alive and in remission for their haematological disease and no hepatitis flares, liver-related death had developed. CONCLUSIONS HCV-positive status may represent a risk factor for the development of hepatic flares in B-cell NHL patients receiving rituximab-containing regimens. Despite the increase in liver function tests, there were no major clinical events.

Chromosomal Aberration of the 11q23 Locus in Acute Leukemia and Frequency of MLL Gene Translocation

Structural abnormality of the 11q23 band (11q23+) bearing the MLL gene translocation (MLL+) is a recurrent chromosome change observed in 3% to 7% of acute lymphoblastic leukemias and in 3% to 4% of acute myeloblastic leukemias. The resolution of conventional cytogenetics (CC) in detecting 11q23 rearrangement is limited when the translocative partner has a telomeric location; furthermore, CC can barely discriminate between true 11q23+/MLL+ and rearrangements clustering within the 11q22 to approximately 25 region without MLL involvement (MLL-). We characterized a series of 378 consecutive patients with adult acute leukemia by using CC, fluorescence in situ hybridization (FISH), and multiplex karyotyping (M-FISH) analysis. Our aim was to define the frequency of cryptic MLL+ cases and the frequency of MLL+ within 11q22 to approximately 25+ cases. As expected, FISH was more sensitive than CC in detecting MLL+ cases, but rather unexpectedly, 9 (45%) of 20 patients with 11q22 to approximately 25+ were MLL-. A better characterization of 11q22 to approximately 25+/MLL- leukemias is relevant for the identification of new, recurrent translocations. Moreover, these cases should be readily distinguishable from 11q23+/MLL+ cases. We recommend that karyotypic analysis always be complemented by molecular or FISH methods to unravel MLL rearrangements.

Use of interim [18F]fluorodeoxyglucose-positron emission tomography is not justified in diffuse large B-cell lymphoma during first-line immunochemotherapy

Abstract In diffuse large B-cell lymphoma (DLBCL), the response to first-line immunochemotherapy remains somewhat unpredictable. Interim [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) (PET-int) analysis could be an important tool in the prompt shift to intensified regimens. We prospectively evaluated the effectiveness of PET-int carried out at mid-treatment with standard immunochemotherapy in predicting relapse in a series of 85 consecutive patients with DLBCL. PET-int results were dichotomized as positive or negative using the recently validated five-point scale scoring system. This examination was also compared with interim computed tomography (CT-int) and final PET (PET-fin). End-points were: complete remission (CR), positive predictive value (PPV) of refractoriness and relapse, negative predictive value (NPV), overall survival (OS) and progression-free survival (PFS). Observation time was fixed to 24 months unless preceded by a DLBCL-related event. The PPV of PET-int was 58% and the NPV was 77%. CR was correlated with both PET-int and CT-int (p < 0.0001), but in multivariate analysis only CT-int was correlated with CR (p = 0.002). CT-int and PET-fin were predictive of both OS and PFS, whereas PET-int was predictive only of OS (p = 0.013). In Cox regression only PET-fin was predictive for both OS (p = 0.004) and PFS (p = 0.005). PET-int was unable to discriminate those chemosensitive patients who would later relapse. We therefore believe that the use of this expensive radioactive tool is not justified as an interim analysis.

Clinicopathologic Characterization of Diffuse-Large-B-Cell Lymphoma with an Associated Serum Monoclonal IgM Component

Recently, diffuse-large-B-cell lymphoma (DLBCL) associated with serum IgM monoclonal component (MC) has been shown to be a very poor prognostic subset although, detailed pathological and molecular data are still lacking. In the present study, the clinicopathological features and survival of IgM-secreting DLBCL were analyzed and compared to non-secreting cases in a series of 151 conventional DLBCL treated with R-CHOP. IgM MC was detected in 19 (12.5%) out of 151 patients at disease onset. In 17 of these cases secretion was likely due to the neoplastic clone, as suggested by the expression of heavy chain IgM protein in the cytoplasm of tumor cells. In IgM-secreting cases immunoblastic features (p<.0001), non-GCB-type (p = .002) stage III-IV(p = .003), ≥2 extra nodal sites (p<.0001), bone-marrow (p = .002), central-nervous-system (CNS) involvement at disease onset or relapse (p<.0001), IPI-score 3–5 (p = .009) and failure to achieve complete remission (p = .005), were significantly more frequent. FISH analyses for BCL2, BCL6 and MYC gene rearrangements detected only two cases harboring BCL2 gene translocation and in one case a concomitant BCL6 gene translocation was also observed. None of the IgM-secreting DLBCL was found to have L265P mutation of MYD88 gene. Thirty-six month event-free (11.8% vs 66.4% p<.0001), progression-free (23.5% vs 75.7%, p<.0001) and overall (47.1% vs 74.8%, p<.0001) survivals were significantly worse in the IgM-secreting group. In multivariate analysis IgM-secreting (p = .005, expB = 0.339, CI = 0.160-0.716) and IPI-score 3–5 (p = .010, expB = 0.274, CI = 0.102–0.737) were the only significant factors for progression-free-survival. Notably, four relapsed patients, who were treated with salvage immmunochemotherapy combined with bortezomib or lenalidomide, achieved lasting remission. Our data suggests that IgM-secreting cases are a distinct subset of DLBCL, originating from activated-B-cells with terminally differentiated features, prevalent extra nodal dissemination and at high risk of CNS involvement.

New reciprocal translocation t(6;10) (q27;q11) associated with idiopathic myelofibrosis and eosinophilia

Idiopathic myelofibrosis (IM), is a chronic myeloproliferative disorder (MPD) characterised by marrow fibrosis, extramedullary haematopoiesis and a leuco-erythroblastic picture of the peripheral blood. Cytogenetic data of IM is scarce: no specific karyotypic anomalies have been yet described. Trisomy 1q, del(13q), del(20q) and trisomy 8, appear in two-thirds of the cases with chromosome aberrations. We report on a 41-year-old patient diagnosed with IM associated with eosinophilia, bearing a novel translocation t(6;10)(q27;q11) as the sole chromosome anomaly. The patient, progressed to AML-M5a within 18 months from diagnosis. Recently new specific chromosomal translocations have been described in chronic MPD. These findings have allowed the classification of new syndromes with defined molecular abnormalities. The case we describe, because of the peculiar clinical features and the association with a previously unreported chromosomal translocation, might be a noteworthy addition.

Tumor-associated and immunochemotherapy-dependent long-term alterations of the peripheral blood NK cell compartment in DLBCL patients

Natural Killer (NK) cells are a key component of tumor immunosurveillance and thus play an important role in rituximab-dependent killing of lymphoma cells via an antibody-dependent cellular cytotoxicity (ADCC) mechanism. We evaluated the phenotypic and functional assets of peripheral blood NK cell subsets in 32 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients and in 27 healthy controls. We further monitored long-term modifications of patient NK cells for up to 12 months after rituximab-based immunochemotherapy. At diagnosis, patients showed a higher percentage of CD56dim and CD16+ NK cells, and a higher frequency of GrzB+ cells in CD56dim, CD56bright, and CD16+ NK cell subsets than healthy controls. Conversely, DLBCL NK cell killing and interferon γ (IFNγ) production capability were comparable to those derived from healthy subjects. Notably, NK cells from refractory/relapsed patients exhibited a lower “natural” cytotoxicity. A marked and prolonged therapy-induced reduction of both “natural” and CD16-dependent NK cytotoxic activities was accompanied by the down-modulation of CD16 and NKG2D activating receptors, particularly in the CD56dim subset. However, reduced NK cell killing was not associated with defective lytic granule content or IFNγ production capability. This study firstly describes tumor-associated and therapy-induced alterations of the systemic NK cell compartment in DLBCL patients. As these alterations may negatively impact rituximab-based therapy efficacy, our work may provide useful information for improving immunochemotherapeutic strategies.

A Novel t(11;12)(q23–24;q24) in a Case of Minimally-Differentiated Acute Myeloid Leukemia (AML-M0)

Acute myeloid leukemia with minimal signs of myeloid differentiation (AML-M0) is a recent addition to the FAB group classification. Chromosome data is scarce, but existing reports describe a high incidence of complex karyotypes and myelodysplastic syndrome-like chromosome alterations, while single chromosome translocations have rarely been reported. We describe the case of a 60-year-old woman diagnosed with AML-M0 with a novel translocation t(11;12)(q23-24;q24) as the sole karyotypic marker. Fluorescence in situ hybridization analysis to assess MLL gene splitting did not show rearrangement of this oncogene.

‘Les liaisons dangereuses’: Hepatitis C, Rituximab and B-cell non-Hodgkin’s lymphomas

Rituximab has provided a revolutionary contribution to the treatment of B-cell non-Hodgkins lymphomas (NHL). A high prevalence of hepatitis C virus (HCV) infection has been described in B-cell NHL patients. Cases of liver dysfunction in HCV-positive patients have been reported with Rituximab-containing regimens. In this paper we review the recent data regarding the effects of Rituximab in NHL patients with HCV infection. We also added a section devoted to improving communication between oncohaematologists and hepatologists. Furthermore, we propose a common methodological ground to study hepatic toxicity emerging during chemotherapy.