Serum albumin level at diagnosis of diffuse large B‐cell lymphoma: an important simple prognostic factor

This study compared the value of several simple laboratory parameters with known prognostic models for predicting survival in patients with diffuse large B‐cell lymphoma (DLBCL). The data of 157 adult patients with DLBCL diagnosed at Rabin Medical Center in 2004–2008 and treated with R‐CHOP immunochemotherapy were retrospectively reviewed. Main clinical features of the cohort were as follows: mean age 63.0 years, 43% male, 63% stage III/IV disease, 28% ECOG performance status > 2, 60% elevated lactate dehydrogenase level. Median duration of follow‐up was 6.6 years. The NCCN‐International Prognostic Index (IPI) was found to be a more powerful prognosticator than the IPI. Five‐year overall survival (OS) was 69.6; 73.6% for patients with intermediate NCCN‐IPI and 38.4% for patients with poor NCCN‐IPI. On univariate analysis, pretreatment hemoglobin and albumin levels were significantly associated with survival. By albumin level, 5‐year OS was 77.6 + 4% in patients with >3.5 g/dl and 53 + 7% in patients with < 3.5 g/dl (p < 0.001); 5‐year progression‐free survival (PFS) was 69.9% and 50.9%, respectively (p = 0.002). By hemoglobin level, 5‐year OS was 82.9 + 4.5% in patients with >12 g/dl and 58.8 + 5% in patients with < 12 g/dl (p = 0.007); 5‐year PFS was 75.5% and 54.1%, respectively (p = 0.008). On multivariate analysis with Cox regression, pretreatment albumin level was a significant independent predictor of OS. Furthermore, 5‐year OS of patients with a high NCCN‐IPI and albumin < 3.5 g/dl was 29.2% compared with 60% in patients with albumin > 3.5 g/dl (p = 0.022). In conclusion, pretreatment albumin level is a strong prognostic factor for OS in patients with DLBCL and can discriminate high‐risk patients for good and poor prognosis. Copyright © 2015 John Wiley & Sons, Ltd.     

Screening for adenoviruses in haematological neoplasia: High prevalence in mantle cell lymphoma

Human adenoviruses possess oncogenic capacity which is well documented in mammalian animal models, but their possible implication in human malignancy has remained enigmatic. Following primary infection, adenoviruses can persist in a latent state in lymphocytes where the virus is apparently able to evade immune surveillance. In the present study, we have employed a broad-spectrum adenovirus polymerase chain reaction (PCR) assay to systematically screen more than 200 diagnostic specimens of different lymphoid malignancies including acute lymphocytic leukaemia (n = 50), chronic lymphocytic leukaemia (n = 50), various types of malignant lymphoma (n = 100) and multiple myeloma (n = 11) for the presence of adenoviral sequences. While most entities analysed revealed negative findings in virtually all specimens tested, adenoviral DNA was detected in 15/36 (42%) mantle cell lymphomas investigated. The most prevalent adenoviral species detected was C, and less commonly B. Adenovirus-positive findings in patients with mantle cell lymphoma were made at different sites including bone marrow (n = 7), intestine (n = 5), lymph nodes (n = 2) and tonsillar tissue (n = 1). The presence of adenoviral sequences identified by PCR was confirmed in individual cells by fluorescence in-situ hybridisation (FISH). The frequent observation of adenoviruses in mantle cell lymphoma is intriguings, and raises questions about their possible involvement in the pathogenesis of this lymphoid malignancy.     

Evaluation of the prognostic role of tumour‐associated macrophages in newly diagnosed classical Hodgkin lymphoma and correlation with early FDG‐PET assessment

In Hodgkin Lymphoma (HL), about 20% of patients still have relapsed/refractory disease and late toxic effects rate continue to rise with time. ‘Early FDG‐PET’ and tissue macrophage infiltration (TAM) emerged as powerful prognostic predictors. The primary endpoint was to investigate the prognostic role of both early FDG‐PET and TAM; the secondary endpoint was to test if early FDG‐PET positivity could correlate with high TAM score. A cohort of 200 HL patients was analysed. Induction treatment plan consisted of two to six courses of ABVD and, if indicated, involved field radiation therapy. All patients repeated CT scan and FDG‐PET after two cycles and after the completion of therapy. TAM in diagnostic specimens was determined by immunohistochemistry with a monoclonal antibody (anti‐CD68 KP1). Overall, early FDG‐PET was negative in 163 patients (81.5%) and positive in 37 patients (18.5%), showing a significant correlation with the achievement of CR (p < 0.0001). After a median follow‐up of 40 months, progression free survival (PFS) was significantly better for PET negative patients (p < 0.0001). CD68 expression was low, intermediate or high in 26 (13%), 100 (50%) and 74 (37%) cases, without difference in the distribution between responders and non‐responders. PFS analysis showed no significant difference in any score group. TAM score did not show any correlation with early FDG‐PET result. This study confirms that early FDG‐PET has a high prognostic power, while TAM score does not seem to influence the outcome; in contrast to our original hypothesis, it does not correlate with FDG‐PET assessment. Copyright © 2015 John Wiley & Sons, Ltd.     

Proliferation predicts failure‐free survival in mantle cell lymphoma patients treated with rituximab plus hyperfractionated cyclophosphamide,vincristine, doxorubicin,and dexamethasone alternating with rituximab plus high‐dose methotrexate and cytarabine

BACKGROUND:

It has been demonstrated that the tumor proliferation index has prognostic significance in patients with mantle cell lymphoma (MCL). Patients in most of studies, however, have been treated with relatively traditional chemotherapy regimens. At the authors' institution, patients with MCL received an aggressive chemotherapy regimen: rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with rituximab plus high‐dose methotrexate and cytarabine (R‐hyper‐CVAD).

METHODS:

The authors assessed the proliferation rate of MCL using immunohistochemistry and an antibody specific for Ki‐67 in 71 untreated patients who subsequently received R‐hyper‐CVAD. The study group included 59 patients who had classic MCL and 12 patients who had the blastoid variant of MCL.

RESULTS:

For the entire study group and for the group of patients with classic MCL, a proliferation index of >20% Ki‐67‐positive cells was correlated significantly with shorter failure‐free survival. There was no correlation between the proliferation index and overall survival.

CONCLUSIONS:

The current results indicated that the proliferation index in patients with MCL predicted prognosis in those who uniformly received the R‐hyper‐CVAD chemotherapy regimen. Cancer 2009. © 2009 American Cancer Society.     

Durable complete responses from therapy with combined epratuzumab and rituximab: final results from an international multicenter, phase 2 study in recurrent, indolent, non-Hodgkin lymphoma

BACKGROUND: In this international, multicenter trial, the authors evaluated rituximab (anti-CD20) plus epratuzumab (anti-CD22) in patients with postchemotherapy relapsed/refractory, indolent non-Hodgkin lymphoma (NHL), including long-term efficacy. METHODS: Forty-nine patients with follicular NHL (FL) (N = 41) or small lymphocytic lymphoma (SLL) (N = 7) received intravenous epratuzumab 360 mg/m2 and then intravenous rituximab 375 mg/m2 weekly x4. The regimen was tolerated well. RESULTS: Twenty-two of 41 patients with FL (54%) had an objective response (OR), including 10 (24%) complete responses (CR) (CR/unconfirmed CR [CRu]), whereas 4 of 7 patients with SLL (57%) had ORs, including 3 (43%) with CR/CRu. Rituximab-naive patients (N = 34) had an OR rate of 50% (26% CR/CRu rate), whereas patients who previously responded to rituximab (N = 14) had an OR rate of 64% (29% CR/CRu rate). An OR rate of 85% was observed in patients with FL who had Follicular Lymphoma International Prognostic Index (FLIPI) risk scores of 0 or 1 (N = 13), whereas 28 patients with intermediate or high-risk FLIPI scores (> or =2) had an OR rate of 39% (18% CR/CRu rate). In patients with FL, the median response duration was 13.4 months, and that duration increased to 29.1 months for 10 patients who had a CR/CRu, including 4 patients who had durable responses with remissions that continued for >4 years. In patients with SLL, the median response duration was 20 months, including 1 patient who had a response that continued for >3 years. CONCLUSIONS: The combination of epratuzumab and rituximab induced durable responses in patients with recurrent, indolent NHL.     

Serum beta‐2 microglobulin as a prognostic biomarker in patients with mantle cell lymphoma

Although serum beta‐2 microglobulin (B2M) has been suggested as a prognostic factor for mantle cell lymphoma (MCL), additional data are necessary to confirm its role. Between November 2005 and July 2014, a total of 52 patients with MCL were identified from the database of Asan Medical Center, Seoul, Korea. Pretreatment serum B2M information was available in 50 patients (96%). Overall survival (OS) was compared according to the serum B2M level with a cut‐off value of 2.5 mg/L. The median MCL international prognostic index (MIPI) score was 5.84 (range 4.72–7.80), and the median biologic MIPI (MIPI‐b) score was 6.27 (4.93–8.47). Pretreatment serum B2M was elevated in 30 patients (60%) and was significantly related to advanced stage (p = 0.02) and high MIPI (p = 0.03) and MIPI‐b (p = 0.03) scores. With median follow‐up duration of 29.8 months (range 0.8–87.0 months), the median OS was 56.2 months [95% confidence interval (CI) 36.6‐75.9 months] in all patients, and serum B2M was significantly associated with OS (p = 0.001). In multivariate analyses adjusted for MIPI or MIPI‐b scores and rituximab, elevated serum B2M was significantly associated with poor OS (when adjusting MIPI, hazard ratio = 26.4, 95% CI 2.9–241.3, p = 0.004; when adjusting MIPI‐b, hazard ratio = 20.1, 95% CI 2.4–170.1, p = 0.006). Thus, pretreatment serum B2M may be an independent and significant prognostic factor in patients with MCL. Copyright © 2015 John Wiley & Sons, Ltd.     

Absolute monocytosis at diagnosis correlates with survival in diffuse large B‐cell lymphoma—possible link with monocytic myeloid‐derived suppressor cells

Some patients with lymphoma have monocytosis at diagnosis, but its significance is unclear. The recently recognized subpopulation, monocytic myeloid‐derived suppressor cells (M‐MDSCs), has immunoregulatory function, suppresses host anti‐tumour immunity and plays a role in cancer tolerance. Data from 91 untreated patients with diffuse large B‐cell lymphoma (DLBCL) were evaluated for monocytosis >1000/mm³ at diagnosis and its significance compared with a number of well‐established prognostic factors for DLBCL including age, stage, gender, B symptoms, extranodal sites, LDH and CRP levels, bone marrow involvement and International Prognostic Index (IPI) score. In 23 of these patients with DLBCL and 15 healthy controls, the proportion of M‐MDSCs in the peripheral blood was determined by flow cytometry. Monocytosis was found in 17.6% of the patient cohort examined. In the multivariate analysis, bone marrow involvement, IPI score and monocytosis were the only independent prognostic factors seen to be associated with decreased progression free and overall survival. Patients with DLBCL had on average increased M‐MDSCs counts at diagnosis compared with controls, which returned to normal after achieving remission. In conclusion, monocytosis was identified as an independent prognostic factor in DLBCL and correlated with worse overall survival. The significant increases in the M‐MDSCs pool observed in some of the cases examined may possibly help to explain why monocytosis is associated with poor outcome in these patients. Copyright © 2012 John Wiley & Sons, Ltd.     

High incidence of MYC and BCL2 abnormalities in mantle cell lymphoma,although only MYC abnormality predicts poor survival

The incidence and prognostic role of MYC and BCL2 rearrangements in mature B-cell lymphomas have been extensively studied, except the infrequent mantle cell lymphoma (MCL). Here, we analyzed the MYC and BCL2 abnormalities and other cytogenetic aberrations by fluorescence in situ hybridization (FISH) in 50 MCL patients with bone marrow involvement. Eighteen patients (36.0%) had MYC gains and/or amplifications, and twelve patients (24.0%) had BCL2 gains and/or amplifications. Among the 18 patients with MYC abnormality, four had simultaneous MYC translocations, but no BCL2 translocation was detected among patients with BCL2 abnormality. Only two patients (4.0%) had both MYC and BCL2 abnormalities. The patients with a MYC abnormality had a significantly higher tumor burden, a higher percentage of medium/high risk MIPI group and genomic instability compared to those without this abnormality. However, no significant difference was observed between patients with or without a BCL2 abnormality in terms of clinical and cytogenetic factors. Patients with a MYC abnormality had poorer progress-free survival (PFS) (9.0 vs. 48.0 months, p = .000) and overall survival (OS) (12.0 vs. 94.5 months, p = .000), but the presence of a BCL2 abnormality did not significantly influence either PFS or OS. In multivariate analysis, the MYC abnormality was the independent adverse factor for both PFS and OS, and intensive chemotherapy did not improve the outcome of these patients. Thus, the presence of a MYC but not BCL2 abnormality predicted the poor survival of MCL patients, and a new treatment strategy should be developed for these patients.     

The ratio of the absolute lymphocyte count to the absolute monocyte count is associated with prognosis in Hodgkin's lymphoma: correlation with tumor-associated macrophages

Background.

Although most patients with classical Hodgkin''s lymphoma (cHL) have a long survival duration, the current risk stratification is imperfect. A recent study suggested a prognostic role for the peripheral blood absolute lymphocyte count/absolute monocyte count (ALC/AMC) ratio at diagnosis in cHL. It is intriguing to investigate the significance of the ALC/AMC ratio in relation to tumor-associated macrophages (TAMs), yet another prognostic factor for cHL.

Methods.

We examined the prognostic impact of the ALC, AMC, and ALC/AMC ratio in 312 cHL patients (median age, 37 years) using receiver operating characteristic curve analysis for optimal cutoff values, and compared these with TAM content.

Results.

The median follow-up was 65 months (range, 0.1–245 months). On univariate analysis, a low ALC/AMC ratio (<2.9) was correlated with a poorer overall survival (OS) outcome. A subgroup analysis of patients with limited-stage disease showed that the ALC/AMC ratio was significantly correlated with the OS time. Multivariate analysis showed the ALC/AMC ratio to be an independent prognostic factor for OS outcome. A Spearman correlation test of TAM content showed a negative correlation with the ALC/AMC ratio and a positive correlation with the peripheral blood macrophage percentage.

Conclusions.

This study suggests that the ALC/AMC ratio may be a simple, inexpensive, and independent prognostic factor for OS outcome in patients with cHL and may have a role in the stratification of cHL patients in addition to the International Prognostic Score and TAM content.     

Pharmacokinetic profile and first preliminary clinical evaluation of bendamustine in Taiwanese patients with heavily pretreated indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Prior studies found bendamustine is efficacious in patients with indolent B‐cell non‐Hodgkin lymphoma (NHL). To date, no studies have reported the efficacy of bendamustine in a Chinese population. This multicentre phase II trial evaluated the pharmacokinetics (PK), safety and efficacy of bendamustine monotherapy in Chinese patients in Taiwan with pretreated indolent B‐cell NHL or mantle cell lymphoma (MCL). For PK assessments, patients were randomized (n = 16; 11 with indolent B‐cell NHL and five with MCL) to 90 or 120 mg/m² of bendamustine for the first cycle. Plasma levels of bendamustine and its two metabolites were analyzed. For efficacy and safety evaluations, bendamustine 120 mg/m² was given to all patients every 3 weeks starting at cycle 2 for a minimum of a total of six cycles. The median age of patients was 61.7 years, and the majority were men (75%). The median number of prior treatments was 4 (range, 1–9 regimens), and all patients were previously treated with rituximab. Bendamustine plasma concentration peaked near the end of infusion and was rapidly eliminated with a mean elimination half‐life (t_1/2) of 0.67–0.8 h. Of the evaluable patients (n = 14), the overall response rate was 78.6%, including 7.2% of patients having a complete response. Mean progression‐free survival was 27.5 weeks. The most common grade 3–4 adverse events were leucopenia (56.3%), neutropenia (56.3%) and thrombocytopenia (25%). In conclusion, bendamustine was efficacious and well tolerated in Taiwanese patients with indolent NHL and MCL with a similar PK profile to that of other populations. Copyright © 2014 John Wiley & Sons, Ltd.     

Real-time quantitative RT-PCR of cyclin D1 mRNA in mantle cell lymphoma: comparison with FISH and immunohistochemistry

Presence of the balanced translocation t(11;14)(q13;q32) and the consequent overexpression of cyclin D1 found in mantle cell lymphoma (MCL) has been shown to be of important diagnostic value. Although many molecular and immunohistochemical approaches have been applied to analyze cyclin D1 status, correlative studies to compare different methods for the diagnosis of MCL are lacking. In this study, we examined 39 archived paraffin specimens from patients diagnosed with a variety of lymphoproliferative diseases including nine cases meeting morphologic and immunophenotypic criteria for MCL by: (1) real-time quantitative RT-PCR to evaluate cyclin D1 mRNA expression; (2) dual fluorescence in situ hybridization (FISH) to evaluate the t(11;14) translocation in interphase nuclei; and (3) tissue array immunohistochemistry to evaluate the cyclin D1 protein level. Among the nine cases of possible MCL, seven cases showed overexpression of cyclin D1 mRNA (cyclin D1 positive MCL) and two cases showed no cyclin D1 mRNA increase (cyclin D1 negative "MCL-like"). In six of seven cyclin D1 positive cases, the t(11;14) translocation was demonstrated by FISH analysis; in one case FISH was unsuccessful. Six of the seven cyclin D1 mRNA overexpressing cases showed increased cyclin D1 protein on tissue array immunohistochemistry; one was technically suboptimal. Among the two cyclin D1 negative MCL-like cases, FISH confirmed the absence of the t(11;14) translocation in both cases. All other lymphoproliferative diseases studied were found to have low or no cyclin D1 mRNA expression and were easily distinguishable from the cyclin D1 overexpressing MCLs by all three techniques. In addition, to confirming the need to assess cyclin D1 status, as well as, morphology and immunophenotyping to establish the diagnosis of MCL, this study demonstrates good correlation and comparability between measure of cyclin D1 mRNA, the 11;14 translocation and cyclin D1 protein.     

Mean platelet volume predicts prognosis in patients with diffuse large B‐cell lymphoma

To determine the prognostic value of baseline mean platelet volume (MPV) in diffuse large B‐cell lymphoma (DLBCL) patients. We retrospectively analyzed 161 DLBCL patients who received R‐CHOP chemotherapy. The associations between MPV and clinicopathological factors were assessed. A low MPV (MPV ≤ 9.1 fl, cut‐off was calculated by receiver operating characteristics) was not associated with any other clinicopathological factors. * Patients with MPV ≤ 9.1 fl experienced a shorter progression‐free survival (PFS) (2‐year PFS rate, 60.6% vs 84.0%, P = 0.003) and overall survival (OS) (2‐year OS rate, 70.4% vs 87.9%, P = 0.030), compared with those with MPV > 9.1 fl. The multivariate analysis demonstrated that MPV ≤ 9.1 fl was an independent prognostic factor of OS (Hazard Ratio [HR] = 0.588, P = 0.045) and PFS (HR = 0.456, P = 0.010). Therefore, we demonstrated that low baseline MPV is an independent prognostic marker of poor outcome in patients with DLBCL.     

Bruton tyrosine kinase is commonly overexpressed in mantle cell lymphoma and its attenuation by Ibrutinib induces apoptosis

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that characteristically shows overexpression of cyclin-D1 due to an alteration in the t(11;14)(q13;q32) chromosomal region. Although there are some promising treatment modalities, great majority of patients with this disease remain incurable. The B-cell antigen receptor (BCR) signaling plays a crucial role in B-cell biology and lymphomagenesis. Bruton tyrosine kinase (BTK) has been identified as a key component of the BCR signaling pathway. Evidence suggests that the blockade of BTK activity by potent pharmacologic inhibitors attenuates BCR signaling and induces cell death. Notably, the expression levels and the role of BTK in MCL survival are still elusive. Here, we demonstrated a moderate to strong BTK expression in all MCL cases (n = 19) compared to benign lymphoid tissues. Treatment of MCL cell lines (Mino or Jeko-1) with a potent BTK pharmacologic inhibitor, Ibrutinib, decreased phospho-BTK-Tyr²²³ expression. Consistent with this observation, Ibrutinib inhibited the viability of both Mino and JeKo-1 cells in concentration- and time-dependent manners. Ibrutinib also induced a concentration-dependent apoptosis in both cell lines. Consistently, Ibrutinib treatment decreased the levels of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1 protein. These findings suggest that BTK signaling plays a critical role in MCL cell survival, and the targeting of BTK could represent a promising therapeutic modality for aggressive lymphoma     

Outcome of patients older than 80 years with diffuse large B‐cell lymphoma (DLBCL) treated with “standard” immunochemotherapy: A large retrospective study from 4 institutions

Little information is available on the very elderly patients with diffuse large B‐cell lymphoma (DLBCL). We performed a retrospective analysis of 281 patients >80 years old with newly diagnosed DLBCL treated in 4 referral institutions in Switzerland and Northern Italy. Primary end points were overall survival, progression‐free survival, and cause‐specific survival. Systemic chemotherapy was given to 239 patients, and 119 of them received rituximab in their initial treatment. At a median follow‐up of 5.5 years, 5‐year progression‐free survival was 26% (95% confidence interval [CI], 20‐32%), 5‐year overall survival was 31% (95% CI, 25‐37%), and 5‐year cause‐specific survival was 48% (95% CI, 41‐55%) for the entire cohort. Rituximab and/or anthracyclines as part of initial treatment were associated with improved outcome. Cause‐specific survival in patients receiving both agents approximated 60% at 5 years. At multivariate analysis, rituximab use maintained a significant prognostic impact after controlling for age, performance status, stage, haemoglobin, and lactate dehydrogenase levels. The International Prognostic Index as well as the more recently proposed revised‐International Prognostic Index and National Comprehensive Cancer Center Network–International Prognostic Index could discriminate patients with significantly different outcomes. Albeit very elderly and potentially frail, there may be a potential for cure in fit DLBCL patients ≥80 years old. Accurate selection of patients able to tolerate proper immunochemotherapy is crucial.     

Expression of methylation-related genes is associated with overall survival in patients with non-small cell lung cancer

The abnormality of DNA methylation is involved in tumour progression, and thus has a modulating effect on clinical outcome of cancer patients. In this study, we measured the mRNA expression levels of three methylation-regulating genes (DNMT1, DNMT3b, and MBD2) in 148 tumour samples from patients with non-small cell lung cancer (NSCLC) using quantitative real-time polymerase chain reaction and then determined their prognostic values. Our data showed that the high level of DNMT1 expression was significantly associated with an increased risk of death in all NSCLC patients (hazard ratio (HR), 1.74; 95% confidence interval (95% CI), 1.04-2.90). However, the high level of DNMT3b expression was significantly associated with poor prognosis only in young patients (<65 years). The high level of MBD2 expression had a significantly reduced risk for death only in male patients and in squamous cell lung carcinoma (SQLC) patients. All three combination groups with DNMT1 and DNMT3b, DNMT1 and MBD2 or DNMT3b and MBD2 revealed significant combined effects in male patients and SQLC patients. Our results suggest that DNMT1, DNMT3b, and MBD2 may play important roles in modulating NSCLC patient survival and thus be useful for identifying NSCLC patients who would benefit most from aggressive therapy.     

Impact of comorbidity on survival in peripheral T‐cell lymphomas: A Swedish Lymphoma Registry study

Comorbidity impacts survival in B‐cell lymphoma patients, but the influence in peripheral T‐cell lymphomas (PTCLs) has been little studied. To investigate the impact of comorbidity on outcome in PTCL, we identified adult patients with newly diagnosed PTCL from 2000 to 2009 in the Swedish Lymphoma Registry. Data on comorbidity at diagnosis were retrospectively collected according to the Charlson Comorbidity Index (CCI). Comorbid conditions were present in 263 out of 694 (38%) patients. A CCI score of ≥2 was associated with inferior overall survival (OS) (hazard ratio [HR] 1.63, P < .001) and progression‐free survival (HR 1.54, P < .001) in multivariate analysis. In patients undergoing front‐line autologous stem cell transplantation (auto SCT), CCI >0 was associated with inferior OS (HR 2.40, P = .013). Chemotherapy regimens were classified as curative or low‐intensity treatments. Among patients aged ≥75 years (n = 214), low‐intensity and curative treatment groups had similar OS (HR 0.8, P = .6), also when adjusted for CCI. In summary, our results demonstrate CCI to be independently associated with survival in PTCLs. Even limited comorbidity impacted survival after front‐line auto SCT, which needs to be considered in treatment decisions. Intensive anthracycline‐based chemotherapy in elderly PTCL patients might be of limited benefit.     

BCL2 mutation spectrum in B‐cell non‐Hodgkin lymphomas and patterns associated with evolution of follicular lymphoma

BCL2 is a target of somatic hypermutation in t(14;18) positive and also in a small fraction of t(14;18) negative diffuse large B‐cell lymphoma (DLBCL), suggesting an aberrant role of somatic hypermutation (ASHM). To elucidate the prevalence of BCL2 mutations in lymphomas other than DLBCL, we Sanger‐sequenced the hypermutable region of the BCL2 gene in a panel of 69 mature B‐cell lymphomas, including Richter's syndrome DLBCL, marginal‐zone lymphomas, post‐transplant lymphoproliferative disorders, HIV‐associated and common‐variable immunodeficiency‐associated DLBCL, all known to harbour ASHM‐dependent mutations in other genes, as well as 16 t(14,18) negative and 21 t(14;18) positive follicular lymphomas (FLs). We also investigated the pattern of BCL2 mutations in longitudinal samples from 10 FL patients relapsing to FL or transforming to DLBCL (tFL). By direct sequencing, we found clonally represented BCL2 mutations in 2/16 (13%) of t(14;18) negative FLs, 2/16 (13%) HIV‐DLBCLs, 1/9 (11%) of Richter's syndrome DLBCL, 1/17 (6%) of post‐transplant lymphoproliferative disorders and 1/2 (50%) common‐variable immunodeficiency‐associated DLBCL. The proportion of mutated cases was significantly lower than in FLs carrying the t(14;18) translocation (15/21, 71%). However, the absence of t(14;18) by FISH or PCR and the molecular features of the mutations strongly suggest that BCL2 represents an additional target of ASHM in these entities. Analysis of the BCL2 mutation pattern in clonally related FL/FL and FL/tFL samples revealed two distinct scenarios of genomic evolution: (i) direct evolution from the antecedent FL clone, with few novel clonal mutations acquired by the tFL major clone, and (ii) evolution from a common mutated long‐lived progenitor cell, which subsequently acquired distinct mutations in the FL and in the relapsed or transformed counterpart. Copyright © 2014 John Wiley & Sons, Ltd.