Journal: Hematological oncology
Mantle cell lymphoma (MCL) is characterized by a variable clinical course in which patients can experience indolent disease or frequent relapses despite a good initial response to conventional therapy. Risk stratification of MCL is most frequently performed using the MCL International Prognostic Index (MIPI). Recent studies indicate that the peripheral blood absolute monocyte count (AMC) and tumour-associated macrophages may reflect the state of the tumour microenvironment in lymphomas. The significance of AMC and tumour-associated macrophages in the clinical course of MCL is unknown. The prognostic impact of the AMC, of CD68 expression and of CD163 expression was retrospectively examined in 103 MCL samples using the receiver operating characteristic curved. Patients with an AMC ≥ 375 cells/μL at diagnosis were more likely to present with advanced-stage disease (p = 0.026), leukocytosis (p < 0.001), lymphocytosis (p = 0.01) and granulocytosis (p = 0.003). On univariate analysis, a high AMC (≥375 cells/μL) correlated with poorer overall survival (OS) (p = 0.01). Neither CD68 nor CD163 expression was significantly associated with either OS or event-free survival. Multivariate analysis showed that a high AMC was a prognostic factor for OS, independent of the MIPI [hazards ratio (HR), 1.811; 95% confidence interval, 1.018-3.223; p = 0.043]. This study demonstrates that the AMC at the time of diagnosis is an independent prognostic factor for OS in MCL, which suggests the possibility that AMC may be used in addition to the MIPI to predict outcome in patients with MCL. Copyright © 2013 John Wiley & Sons, Ltd.
The diagnosis of hemophagocytic lymphohistiocytosis (HLH) is delayed by most physicians. This study aimed to identify early parameters and suitable scoring systems for the risk of HLH. Clinical and laboratory data collected ≤3 days after admission were defined as early parameters and used to calculate the number of HLH-2004 criteria met and bone marrow (BM) score. Between January 2006 and February 2016, 233 immunocompetent adults with naïve fever of unknown origin who underwent a BM study were enrolled to mimic patients at risk of HLH and randomly assigned into the developmental or validation cohort. Hemophagocytic lymphohistiocytosis was finally diagnosed in 47 patients, with non-Hodgkin lymphoma as the major etiology (51.1%). Upon admission, four-fifths of patients who developed subsequent HLH fulfilled ≤3 of 8 HLH-2004 criteria, and 6 early parameters were independent predictors of HLH: anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelet count < 100 × 10(3) /μL), leukoerythroblastosis, hyperbilirubinemia (total bilirubin > 2 × upper normal limit), hyperferritinemia (ferritin > 1000 ng/mL), and splenomegaly. Compared with the HLH criteria met upon admission, the BM score was an independent predictor (odds ratio = 1.621; 95% confidence interval, 1.355-1.940) with excellent discrimination (area under the receiver operating characteristic curve = 0.920; 95% confidence interval, 0.883-0.958). The sensitivity and specificity for a BM score cutoff of 10 points were 95% and 75%, respectively. When approaching immunocompetent adults with a continuously high fever, the BM score at initial admission assists with early identification of patients at risk of HLH.
Leukostasis is a poorly understood and life-threatening complication of acute hyperleukocytic leukemia. The incidence of hyperleukocytosis and leukostasis differs among various subtypes of leukemias. While the pathophysiology of leukostasis is not fully understood, recent research has elucidated many novel pathways that may have therapeutic implications in the future. Respiratory and neurological compromise represents the classical clinical manifestations of leukostasis. If it is not diagnosed and treated rapidly, the one-week mortality rate is approximately 40%. Targeted induction chemotherapy is an important component of the successful treatment of leukostasis, although other modalities of cytoreduction are being used and investigated. Copyright © 2016 John Wiley & Sons, Ltd.
The introduction of new therapeutic agents in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL), including the new kinase inhibitor idelalisib, has changed the therapeutic landscape of these diseases. However, the use of idelalisib is associated with a peculiar profile of side effects, which require an optimization of the current approach to prophylaxis and supportive treatment. Moving from the recognition that the abovementioned issue represents an unmet need in CLL and FL, a multidisciplinary panel of experts was convened to produce a consensus document aiming to provide practical recommendations for the management of the side effects during idelalisib therapy for CLL and FL. The present publication represents a consensus document from a series of meetings held during 2017. The Panel generated clinical key questions using the criterion of clinical relevance through a Delphi process and explored 4 domains, ie, diarrhea/colitis, transaminitis, pneumonitis, and infectious complications. Using the consensus method, the Panel was able to shape recommendations which may assist hematologist to minimize adverse events and guarantee adherence to treatment in patients with CLL and FL candidate to receive idelalisib.
Mucosa associated lymphoid tissue (MALT) lymphoma is an indolent lymphoma with good prognosis and variable 18F-FDG-avidity. Many possible prognostic factors have been investigated with controversial results, but possible prognostic role of 18F-FDG-PET/CT remains unclear. Our aim was to evaluate the prognostic impact of qualitative and semiquantitative baseline PET/CT parameters on outcome of MALT lymphoma. We retrospectively enrolled 161 patients with histologically-confirmed MALT lymphoma who underwent 18F-FDG-PET/CT before any treatment. PET images were qualitatively and semi-quantitatively analyzed by measuring the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). The Kaplan-Meier method was used to estimate the progression-free survival (PFS) and overall survival (OS) times. Cox regression models were performed to determinate the relation between PET/CT features and OS and PFS. Ninety-eight patients had positive 18F-FDG-PET/CT showing 18F-FDG uptake (mean SUVbw 10.1; SUVlbm 7.2; SUVbsa 2.7; MTV 88.8; TLG 526); the remaining 63 were not 18F-FDG avid. 18F-FDG avidity was significantly correlated with tumor size and Ki-67 score. Relapse/progression of disease occurred in 47 patients with an average time of 40.2 months; death occurred in 12 patients with an average of 59 months. At a median follow-up of 62 months, median PFS and OS were 52 and 62 months. Advanced tumor stage and extragastric site were demonstrated to be independent prognostic factors for PFS, while only tumor stage for OS. Instead PET/CT parameters were not related to survival, despite positive correlation at univariate analysis between MTV and TLG with PFS and positive PET/CT with PFS and OS. In conclusion, a 61% rate of PET avidity in biopsy-confirmed MALT lymphoma was found and it was correlated with tumor size and Ki-67 score. Only tumor stage and localization were independently correlated with PFS and OS.
Despite antiretroviral therapy, HIV+ individuals still have increased risk to develop lymphomas, including marginal zone lymphomas, suggesting that factors other than HIV-related immunosuppression are probably acting as lymphomagenic factors in the HIV setting. The possible pathogenic involvement of HIV p17 protein variants was investigated in a particularly informative case of HIV-related splenic marginal zone lymphoma, who was negative for oncogenic virus infections, thus allowing us to assess the possible direct contribution of these HIV-encoded proteins to lymphomagenesis. The presence of p17 protein was analyzed by immunohistochemistry in lymphoma tissue. Recombinant p17 protein derived from the dominant sequence detected in plasma and lymphoma biopsy was characterized for B-cell proliferation, clonogenicity in soft agar, in vitro tube formation and wound-healing. Intracellular signaling was investigated by immunoblotting. HIV p17 protein was detected in reactive lymphoid follicles but not within lymphoma cells. An identical dominant variant p17 sequence, p17-Lyrm, carrying a 117-118 Ala-Ala insertion was detected in both plasma and lymphoma tissue. Recombinant p17-Lyrm enhanced B-cell proliferation and clonogenicity, promoted the formation of capillary-like structures and enhanced endothelial cell migration. Unlike reference p17, the p17-Lyrm variant enhanced the activation of Akt and ERK, critical kinases in lymphomagenesis. p17-Lyrm clonogenic activity was dependent on the activation of Akt but not of ERK1/2. These results indicate the HIV p17 variants with distinct molecular signatures and functional properties may accumulate in lymphoid tissues of HIV-infected individuals where they may act as a local stimulus promoting the development of lymphomas.
Randomized trials of maintenance therapy (MT) in Diffuse Large B-cell Lymphoma (DLBCL) are inconclusive regarding its effect on overall survival (OS) and disease control. We aimed to examine the efficacy and safety of MT in this meta-analysis.
Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate that is highly effective in patients with relapsed/refractory anaplastic large cell lymphoma (ALCL). However, survival outcomes following suboptimal response or subsequent relapse are not well known. We conducted a multicenter study analyzing outcomes of patients with relapsed/refractory ALCL who have received BV with a secondary focus on survival after progression following BV. A total of 56 patients were treated with BV for relapsed or refractory ALCL. The overall response rate to BV was 73% with complete response (CR) rate of 46%. The median failure-free survival and overall survival (OS) after BV were 15.5 month and not reached, respectively. The median duration of response was 27.6 months in patients who achieved CR by BV, while the median OS of those who did not achieve CR by BV was 9.5 months. There was no significant difference in OS between those who underwent stem cell transplant (SCT) and those who did not in patients who achieved CR after BV. However, if patients were in PR after BV, SCT was associated with significantly longer OS. Thirty patients experienced progressive disease on BV or required a subsequent treatment. The median OS after BV failure was 2.9 months with 2-year OS of 27.1%. There were seven long-term survivors (≥ 12months) following failure. After an adequate response to subsequent salvage therapy, five patients underwent subsequent SCT (3 allogeneic and 2 autologous), four of which were long-term survivors (17+, 25+, 32+ and 50+ months). In conclusion, BV failure is associated with a poor outcome in patients with ALCL, which defines a small but important group with unmet need. SCT may have benefit in patients with relapsed/refractory ALCL who failed BV.
The finding of an IgM monoclonal gammopathy often represents a diagnostic challenge. In fact, there are many pathological disorders associated with this condition, each of which has distinctive characteristics and requires specific clinical, instrumental, and laboratory assessments to set the appropriate treatment. This review has two aims. Firstly, to provide a framework of the broad spectrum of IgM-associated disorders: (1) monoclonal gammopathy of undetermined significance (MGUS); (2) Waldenström macroglobulinemia (WM); (3) IgM-related disorders (among which hyperviscosity syndrome, light chain amyloidosis, cold agglutinin disease, cryoglobulinaemia, IgM neuropathy, Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome, Castleman disease); (4) IgM-secreting multiple myeloma (IgM-MM); and (5) other lymphoproliferative disorders which may be associated with IgM (such as chronic lymphocytic leukemia, small lymphocytic lymphoma, and B-cell non Hodgkin lymphoma). Secondly, to give a detailed insight regarding diagnosis and treatment of WM.
The international staging system (ISS) is the most commonly used risk-stratification system for patients with multiple myeloma (MM) and is determined by serum albumin and β2-microglobulin levels. In the two determinants, β2-microglobulin levels are frequently observed to be elevated in patients with myeloma, particularly in those with renal impairment. In comparison with patients with intact immunoglobulin myeloma, patients with LC myeloma do not necessarily show decreased levels of serum albumin. The clinical impact of ISS in patients with LCMM, in particular the distinction between ISS I and II, may be complicated due to non-decreased levels of serum albumin in both stages. Accordingly, we have attempted to assess clinical relevance of the ISS in patients with LC myeloma. The clinical data of 1899 patients with MM diagnosed between January 2001 and December 2012 were collected from 38 affiliated hospitals of the Japanese Society of Myeloma. Significant difference was not found between stage I (n = 72) and stage II (n = 92) in LC myeloma patients (n = 307). The mean serum albumin concentration of patients with LC myeloma was within the reference range but higher than that of patients with IgG + IgA myeloma (n = 1501), which complicates the distinction between ISS stage I and II myeloma. Patients with LC myeloma had low frequencies of t(4; 14) and high frequency of elevated lactate dehydrogenase (LDH), and despite a relevant amount of missing data in our registry (R-ISS stage I; n = 11, stage II; n = 32, and stage III: n = 18), the information included in the R-ISS scoring system seems to be more accurate than ISS to obtain a reliable risk stratification approach in non-ISS stage III LC myeloma patients.