Silvia Montoto

Risk and Clinical Implications of Transformation of Follicular Lymphoma to Diffuse Large B-Cell Lymphoma

PURPOSE To study the clinical significance of transformation to diffuse large B-cell lymphoma (DLBCL) in patients with follicular lymphoma (FL). PATIENTS AND METHODS From 1972 to 1999, 325 patients were diagnosed with FL at St Bartholomews Hospital (London, United Kingdom). With a median follow-up of 15 years, progression occurred in 186 patients and biopsy-proven transformation in 88 of the 325. The overall repeat biopsy rate was 70%. RESULTS The risk of histologic transformation (HT) by 10 years was 28%, HT not yet having been observed after 16.2 years. The risk was higher in patients with advanced stage (P = .02), high-risk Follicular Lymphoma International Prognostic Index (FLIPI; P = .01), and International Prognostic Index (IPI; P = .04) scores at diagnosis. Expectant management (as opposed to treatment being initiated at diagnosis) also predicted for a higher risk of HT (P = .008). Older age (P = .005), low hemoglobin level (P = .03), high lactate dehydrogenase (P < .0001), and high-risk FLIPI (P = .01) or IPI (P = .003) score at the time of first recurrence were associated with the diagnosis of HT in a biopsy performed at that time. The median survival from transformation was 1.2 years. Patients with HT had a shorter overall survival (P < .0001) and a shorter survival from progression (P < .0001) than did those in whom it was not diagnosed. CONCLUSION Advanced stage and high-risk FLIPI and IPI scores at diagnosis correlate with an increased risk of HT. This event strongly influences the outcome of patients with FL by shortening their survival. There may be a subgroup of patients in whom HT does not occur.

Diffuse Large B-Cell Lymphoma: Clinical and Biological Characterization and Outcome According to the Nodal or Extranodal Primary Origin

PURPOSE To study the main clinicobiologic features, response, and outcome of patients with diffuse large B-cell lymphoma (DLBCL) according to the primary site, lymph node, or different extranodal organs of the disease. PATIENTS AND METHODS We included 382 patients consecutively diagnosed with DLBCL in a single institution during a 13-year period. Morphology, immunophenotyping, proliferation index, differentiation profile, bcl-2/JH rearrangement, and clinical characteristics were analyzed according to the primary site of the lymphoma. RESULTS Sites of the disease were: lymph node, 222 cases (58%); Waldeyers ring (WR), 42 (11%); and extranodal sites, 118 (31%), including GI tract in 45 cases. Primary extranodal cases, particularly GI, showed a bcl-6 expression more frequently than nodal cases. Patients with primary WR or GI lymphomas presented with early-stage disease, no marrow infiltration, normal serum lactate dehydrogenase, and low- to low/intermediate-risk international prognostic index (IPI) more frequently than the remainder. Complete response (CR) rate was 63%, with WR and GI lymphomas having a higher CR rate (85% and 80%, respectively) than the other groups. In the whole series, 5-year overall survival (OS) was 52%. Patients with WR or GI lymphomas showed better OS (5-year OS: 77% and 68%, respectively) than patients with nodal or other extranodal sites. In the multivariate analysis, IPI, bulky disease, and beta2-microglobulin were the main variables to predict OS; no nodal or extranodal site maintained their prognostic value. CONCLUSION In the present series, the primary site of disease was associated with particular clinicopathologic features and outcome, though the latter largely depended on other factors.

British HIV Association guidelines for HIV‐associated malignancies 2014

M Bower, S Collins, C Cottrill, K Cwynarski, S Montoto, M Nelson, N Nwokolo, T Powles, J Stebbing, N Wales and A Webb, on behalf of the AIDS Malignancy Subcommittee Department of Oncology, Chelsea & Westminster Hospital, London, UK, HIV i-Base and UK-CAB, London, UK, St Bartholomew’s Hospital, London, UK, Royal Free Hospital, London, UK, Hammersmith Hospital, London, UK and Royal Sussex County Hospital, Brighton, UK

ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL)

To complete the existing treatment guidelines for all tumor types, ESMO organizes consensus conferences to better clarify open issues in each disease. In this setting, a consensus conference on the management of lymphoma was held on 18 June 2011 in Lugano, immediately after the end of the 11th International Conference on Malignant Lymphoma. The consensus conference convened ∼45 experts from all around Europe and selected six lymphoma entities to be addressed; for each of them three to five open questions were to be discussed by the experts. For each question, a recommendation should be given by the panel, supported by the strength of the recommendation based on the level of evidence. This consensus report focuses on the three most common lymphoproliferative malignancies: diffuse large B-cell lymphoma, follicular lymphoma and chronic lymphocytic leukemia. A second report will concentrate on mantle cell lymphoma, marginal zone lymphoma and T-cell lymphomas.

Brief Communication: Rituximab in HIV-Associated Multicentric Castleman Disease

Context Castleman disease is a rare lymphoproliferative condition. Risk for the condition is elevated in people with HIV infection. Case reports and series suggest that rituximab shows some therapeutic promise in patients previously treated with chemotherapy, but data on initial therapy with rituximab are lacking. Contribution This uncontrolled case series suggests that initial treatment with rituximab can achieve better overall and disease-free survival than that anticipated in untreated patients. Laboratory measures improved with therapy. Caution The absence of a control group precludes definitive assessment of the efficacy or safety of rituximab in treating HIV-associated Castleman disease. The Editors Multicentric Castleman disease is a rare lymphoproliferative disorder that is increasingly occurring in people with HIV infection. It is associated with Kaposi sarcoma, sharing an etiologic agent, Kaposi sarcomaassociated herpesvirus (KSHV), also known as human herpesvirus-8 (1, 2). The gold-standard therapy for HIV-associated multicentric Castleman disease is yet to be established. The use of an anti-CD20 monoclonal antibody, rituximab, to target KSHV-infected plasmablasts in multicentric Castleman disease is a novel and potentially beneficial approach. It has been the subject of case reports and clinical series, in which patients were often pretreated with chemotherapy and follow-up was brief (310). We investigated the efficacy and safety of rituximab as initial monotherapy and correlate clinical findings with immune subset, plasma cytokine, and HIV and KSHV virologic variables. Methods Between 2003 and 2006, 21 patients (18 men) with multicentric Castleman disease were treated prospectively in a nonrandomized, open-label, phase II study with 4 infusions of rituximab at a standard dose of 375 mg per m2 of body surface area at weekly intervals. All biopsy specimens were reviewed and confirmed to be plasmablastic variants of multicentric Castleman disease with no microlymphoma, as defined by previous studies (11, 12). The plasmablasts showed immunoglobulin light chain restriction, were KSHV latent nuclear antigenpositive, and expressed CD20 on immunohistochemistry. Patients were recruited from 3 HIV and cancer centers, where local ethics review committees approved the study and patients gave informed consent. Toxicity was recorded at each visit and was graded by using the Common Terminology Criteria for Adverse Events, version 3.0 (13). We measured plasma KSHV DNA viral load at diagnosis and at 1 and 3 months after rituximab therapy by using Lightcycler quantitative polymerase chain reaction (Roche, Lewis, United Kingdom) on DNA extracted from whole blood using primers specific to KSHV ORF-7 gene, as described elsewhere (14). We assessed progression-free and overall survival by using the KaplanMeier method (15) and used the Wilcoxon rank-sum test to assess the statistical significance of changes in hematologic, biochemical, and immunologic variables. Summaries of data that were not normally distributed are presented as medians with interquartile ranges. All P values are 2-sided (Statview, version 4.57, Abacus Concepts, Berkeley, California). Role of the Funding Source Support for the cytokine assays was provided by St. Stephens AIDS Trust, a national charity supporting clinical research in HIV/AIDS, which had no role in the design, conduct, or reporting of this review or in the decision to publish the manuscript. Results We enrolled 21 patients with a histologically confirmed plasmablastic variant of multicentric Castleman disease without microlymphoma. Their median age was 37 years (range, 31 to 69 years), 9 (43%) patients had a previous AIDS-defining diagnosis, and 13 (62%) patients were receiving highly active antiretroviral therapy (HAART) at diagnosis of multicentric Castleman disease. The median CD4 cell count at diagnosis was 0.30109 cells/L (range, 0.08 to 0.73109 cells/L). Four patients had a plasma HIV-1 viral load less than 50 copies/mL, and 5 other patients had a viral load less than 400 copies/mL (Table 1). Table 1. Hematologic, Biochemical, and Immunologic Variables at Presentation and Change from Baseline 1 Month after Completion of Rituximab Therapy* At diagnosis, the median duration of symptoms was 4 months (range, 0.5 to 24 months), all patients had significant lymphadenopathy, 20 (95%) patients had fever of unknown origin, 18 of 20 (90%) patients had splenomegaly (1 had had splenectomy), and 11 (52%) patients had cutaneous Kaposi sarcoma. Ninety-five percent of the patients had an increased erythrocyte sedimentation rate (ESR) (>20 mm/h), 82% had an increased C-reactive protein (CRP) level (>10 mg/L), 67% were anemic (hemoglobin level <100 g/L), 67% were hypoalbuminemic (serum albumin level <30 g/L), and 14% were thrombocytopenic (platelet count <100109 cells/L). All patients had polyclonal hypergammaglobulinemia, and 2 patients had a serum IgG monoclonal paraprotein band (Table 1). One patient who was receiving intensive care at diagnosis died of progressive disease before completing the rituximab course. All 20 remaining patients achieved resolution of symptoms and fever by the end of rituximab treatment. Of the 21 patients, 14 (67%) had a partial response and 6 (29%) had stable disease according to the radiologic Response Evaluation Criteria in Solid Tumors. The median follow-up was 12 months (range, 1 to 49 months). The 2-year overall survival rate was 95% (95% CI, 86% to 100%), and the relapse-free survival rate was 92% (CI, 75% to 100%) at 1 year and 79% (CI, 52% to 100%) at 2 years. One month after completion of rituximab therapy, 0 of 20 patients were anemic, 0 of 20 were thrombocytopenic, 11 of 17 had an increased ESR, 2 of 16 had an increased CRP level, and 1 of 20 had hypoalbuminemia. Hemoglobin level, platelet count, and serum albumin level increased, whereas ESR and CRP level decreased, 1 month after rituximab treatment (Table 1). Quantitative polymerase chain reaction for KSHV was available for 11 patients at diagnosis and was detectable in 9 patients (median, 700 copies/mL; range, 0 to 400000 copies/mL). One month after treatment, only 2 of 10 (20%) patients had detectable KSHV (Table 1). In both cases, the titer was only 100 copies/mL. Three months after rituximab therapy, only 1 of 10 (10%) patients had detectable KSHV DNA, and once again the titer was only 100 copies/mL (P= 0.018). Serum IgG and IgM levels decreased 1 month after rituximab therapy, but IgA levels did not change (Table 1). Similarly, the CD19 cell count decreased, which persisted at 3 months (median decrease from baseline, 104 cells/mL; interquartile range, 14 to 350 cells/mL; P= 0.002), but the CD19 cell count had recovered to prerituximab levels by 12 months. We performed immune subset analysis on the 13 patients who were already receiving HAART at the time of rituximab therapy. The CD4, CD8, CD56 (natural killer) cell subsets, or HIV viral load did not change during this period. No Common Terminology Criteria for Adverse Events grade 3 or 4 toxicities were recorded with rituximab therapy; however, Kaposi sarcoma progressed during rituximab therapy in 4 of 11 (36%) patients who had cutaneous Kaposi sarcoma at diagnosis. We also measured 15 plasma cytokines: interleukin (IL)1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p40/p70, IL-13, IL-15, IL-17, interferon-, interferon-, tumor necrosis factor-, and granulocyte macrophage colony-stimulating factor, before and after rituximab therapy and again 3 months after the completion of rituximab therapy. Most patients had elevated plasma cytokine levels at presentation, and the proportion with increased levels declined on completion of therapy (Table 2). Table 2. Proportion of Patients with Elevated Plasma Cytokine Levels at Diagnosis and Changes during Treatment* Discussion Rituximab therapy seems to be a promising first-line treatment for HIV-associated multicentric Castleman disease: Patients completing 4 weekly infusions achieved a clinical and biochemical remission within 1 month, and the radiologic response rate was 67%. Plasma KSHV viral load significantly decreased in individuals with this measurement (P= 0.018). The 2-year overall survival rate was 95% (CI, 86% to 100%), and the relapse-free survival rate was 79% (CI, 52% to 100%). This compares favorably with the median survival of 14 months recorded for 20 patients from the pre-HAART era (16). The clinical response to rituximab occurred within 1 month of completing therapy, and normalization of acute-phase inflammatory markers, such as ESR, CRP, and albumin, occurred by this point. Plasma KSHV DNA viral load was measured before, during, and after treatment and decreased dramatically with treatment and increased at relapse. The high plasma titers of KSHV reflect lytic replication, which is not a feature of Kaposi sarcoma but correlates with disease activity in multicentric Castleman disease. Indeed, KSHV-infected B-lymphocytes from lymph nodes in patients with multicentric Castleman disease are known to express KSHV lytic gene products (17, 18). Rituximab produced a decrease in CD19-positive B-lymphocytes, as would be expected, but was well tolerated in patients with HIV-related multicentric Castleman disease, with no grade 3 or 4 toxicities. In addition, rituximab did not seem to cause exacerbation of HIV infection, with no adverse effect on the immune T-cell subsets, including CD4 cell count or HIV viral load. However, Kaposi sarcoma progressed in 36% of patients with this disease, a phenomenon that has been recorded previously (4). The reason for this is unclear, but the rapid decrease in B-lymphocytes observed with rituximab therapy may play a role in the progression of Kaposi sarcoma (19). Because rituximab has also been associated with an increased risk for death from infection in AIDS-related non-Hodgkin lymphoma (20), the data we present should provide reassurance to clinicians. A recent trial i

Long-term follow-up of high-dose treatment with autologous haematopoietic progenitor cell support in 693 patients with follicular lymphoma: an EBMT registry study

To evaluate the outcome of a large series of patients who received high-dose treatment (HDT) for follicular lymphoma (FL), 693 patients undergoing HDT (total-body irradiation (TBI)-containing regimen: 58%; autologous bone marrow (BM)/peripheral blood progenitor cells (PBPCs): 378/285 patients) were included in the study. A total of 375 patients (54%) developed recurrent lymphoma, 10-year progression-free survival (PFS) being 31%. On multivariate analysis, younger age (P=0.003) and HDT in first complete remission (CR1) (P<0.001) correlated with longer PFS. With a median follow-up of 10.3 years, 330 patients died. Ten-year overall survival (OS) from HDT was 52%. Shorter OS was associated on multivariate analysis with older age (P<0.001), chemoresistant disease (P<0.001), BM+PBPC as source of stem cells (P=0.007) and TBI-containing regimens (P=0.004). Thirty-nine patients developed secondary myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), in 34 cases having received TBI as the conditioning regimen. The 5-year non-relapse mortality (NRM) was 9%. On multivariate analysis, older age (P<0.001), refractory disease (P<0.001) and TBI (P=0.04) were associated with a higher NRM. This long follow-up study shows a plateau in the PFS curve, suggesting that a selected group of patients might be cured with HDT. On the downside, TBI-containing regimens are associated with a negative impact on survival.

EZH2 mutations are frequent and represent an early event in follicular lymphoma

Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 mutations in a large cohort of patients with follicular lymphoma (FL) (n = 366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n = 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2 with other mutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy.

Transformation of follicular lymphoma to diffuse large B-cell lymphoma may occur by divergent evolution from a common progenitor cell or by direct evolution from the follicular lymphoma clone

To investigate the cell of origin linking follicular (FL) and transformed (t-FL) lymphomas, we analyzed the somatic hypermutation (SHM) pattern of the variable region of the immunoglobulin heavy gene (IgH-VH) in 18 sequential FL/t-FL samples and a father (donor) and son (recipient), who developed FL and t-FL, after transplantation. Genealogic trees showed a pattern compatible with a common progenitor cell (CPC) origin in 13 cases. The identification of the t-FL clonotype in the previous FL sample and of the putative CPC sequence in both the FL/t-FL biopsies showed that the intraclonal diversity of FL and t-FL germinal centers (GCs) is more intricate than previously described, and all 3 clonotypes (CPC, FL, t-FL) may occur simultaneously within the same lymph node. On the basis of the father/son model, this CPC must be long-lived, providing a possible explanation for the incurable nature of this disease.

Transformation of Indolent B-Cell Lymphomas

Histologic transformation (HT) to an aggressive lymphoma is a well-described event in the natural history and clinical course of patients with so-called indolent lymphomas. This phenomenon has been studied most extensively in patients with follicular lymphoma and subsequent transformation to a diffuse large B-cell lymphoma, with little literature on HT in nonfollicular lymphomas. Despite a considerable body of information on the pathologic and molecular events associated with HT, its pathogenesis has remained elusive and the molecular information available has not been translated into clinical advances. It remains unclear if there is already a predisposition to HT and whether this can be detected at the time of diagnosis. The rituximab era has been characterized by a significant improvement in the prognosis of patients with B-cell lymphomas, but HT remains one of the most important challenges in the management of patients with indolent lymphoma, the difficulties starting with the diagnosis and definition of HT and ending with the appropriate management and treatment of the event. Going forward, it is crucial to incorporate HT as a major end point in clinical trials and to include patients with HT as subject of such studies if we are to see meaningful progress in the future.

Smoldering multiple myeloma: natural history and recognition of an evolving type

Summary.  Patients with smoldering multiple myeloma (SMM) meet the diagnostic criteria of multiple myeloma (MM) but are asymptomatic. Between January 1978 and July 2001, 53 patients (median age 63 years) were diagnosed with SMM. The median serum M‐protein and proportion of bone marrow plasma cells were 36 g/l and 27% respectively. Two subsets of SMM were identified: (i) evolving SMM (n = 22), characterized by a progressive increase in serum M‐protein, a previously recognized monoclonal gammopathy of undetermined significance (MGUS) and a significant higher proportion of IgA type and (ii) non‐evolving SMM (n = 26) with stable M‐protein that abruptly increases when symptomatic MM develops. Thirty‐four patients developed symptomatic MM. The median time to progression in the overall series was 3·2 years and the only feature associated with a shorter time to progression was the evolving versus non‐evolving type (1·3 vs. 3·9 years respectively, P = 0·007). The pattern of progression consisted of anaemia, lytic bone lesions or both, without renal failure, hypercalcaemia or extramedullary plasmacytomas. Fifty‐seven per cent of patients that required chemotherapy showed no or minimal response. The median survival from diagnosis and from progression was 8·2 and 3·5 years respectively.