Clinical outcome of Epstein–Barr virus‐positive diffuse large B‐cell lymphoma of the elderly in the rituximab era

Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma. The incidence of Epstein–Barr virus (EBV)‐positive DLBCL in Asian and Latin American countries ranges from 8 to 10%. The prognosis of patients with EBV‐positive DLBCL is controversial. To compare the clinical outcome of EBV‐positive and EBV‐negative patients with DLBCL in the rituximab era, we analyzed 239 patients with de novo DLBCL diagnosed between January 2007 and December 2011. The presence of EBV in lymphoma cells was detected using EBV‐encoded RNA in situ hybridization, and it was found that 18 (6.9%) of 260 patients with diagnosed DLBCL tested positive. Among the 260 cases, 216 cases were treated with rituximab plus chemotherapy, as were 8 EBV‐positive DLBCL patients. The median overall survival and progression‐free survival times in patients with EBV‐positive DLBCL were 8.7 months and 6.8 months, respectively. The median overall survival and progression‐free survival could not be determined in EBV‐negative DLBCL patients (P = 0.0002, P < 0.0001, respectively). The outcome of patients with EBV‐positive DLBCL remains poor, even in the rituximab era.     

Epstein‐Barr virus positivity is associated with angiogenesis in,and poorer survival of,patients receiving standard treatment for classical Hodgkin's lymphoma

Epstein‐Barr virus (EBV) is a significant contributor to the development of classical Hodgkin's lymphoma (cHL). Recent studies have documented associations between angiogenesis and EBV‐associated malignancies. No study has yet examined the associations among, and prognostic implications of, EBV infection, vascular endothelial growth factor (VEGF) expression, and microvessel density (MVD) in cHL patients. Diagnostic tissues from 135 cHL patients treated with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) were retrospectively evaluated by in situ hybridization of EBV‐encoded small RNA (EBER) and immunohistochemical staining for VEGF and CD31 (a measure of MVD). EBER and VEGF expression were positively correlated (P = 0.038). The mean MVD value of EBER‐positive tumors was significantly higher than that of EBER‐negative tumors (P = 0.034). The mean MVD of tumors positive for both EBER and VEGF was significantly higher than that of tumors negative for both markers (P = 0.008). EBER‐positive patients had a lower 5‐year overall survival (OS) rate than EBER‐negative patients (P = 0.046). A high MVD was also associated with a poorer OS (P = 0.01); multivariate analysis showed that this was a significant and independent prognostic factor (P = 0.026). We found positive correlations between EBER and VEGF levels, and the MVD, indicating that EBV plays an important role in tumor angiogenesis. Targeting of both angiogenesis and EBV may be important when treating cHL patients who are EBER‐positive and/or have a high MVD.     

Prognostic significance of Epstein–Barr virus DNA detection in pretreatment serum in diffuse large B‐cell lymphoma

It is still a matter of debate whether detection of Epstein–Barr virus (EBV) DNA in pretreatment serum has clinical implications for diffuse large B‐cell lymphoma. For this study, we measured EBV DNA load in pretreatment serum from 127 diffuse large B‐cell lymphoma patients without any underlying immunodeficiency to evaluate its effects on clinical manifestations and prognosis. Anthracycline‐based chemotherapy in combination with rituximab was given as initial therapy for 119 patients (94%). Epstein–Barr virus DNA was detected in 15 patients (12%), who were older (P = 0.005) and tended to be at a more advanced disease stage (P = 0.053). They showed significantly worse progression‐free survival (PFS) and overall survival (OS) than other patients (P < 0.001 each). This effect remained significant (P = 0.004 and P = 0.027, respectively) after adjustment for age, lactate dehydrogenase, performance status, stage, and extranodal sites. The status of EBV‐encoded small RNA in situ hybridization was known for 123 patients; 6 of 8 positive patients (75%) and 9 of 115 negative patients (8%) had detectable EBV DNA in pretreatment serum. While patients positive for EBV‐encoded small RNA had significantly worse PFS and OS than negative patients (P = 0.001 and P = 0.029, respectively), EBV DNA detection in pretreatment serum was associated with poorer PFS and OS even for the 115 patients negative for EBV‐encoded small RNA (P < 0.001 each). These findings suggest that EBV DNA detection in pretreatment serum may have an adverse prognostic impact for patients with diffuse large B‐cell lymphoma.     

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.     

The role of maintenance therapy in patients with diffuse large B cell lymphoma: A systematic review and meta‐analysis

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. Systematic review and meta‐analysis of randomized controlled trials comparing MT with observation or placebo, in patients with DLBCL, who achieved complete response (CR) or partial response (PR) after first‐line chemotherapy with or without rituximab. Primary outcome was OS. Secondary outcomes included relapse rate, disease control (defined as progression‐free survival, event‐free survival, or disease‐free survival, as reported in the original trials), and safety. Our search yielded 14 trials including 5122 patients. Median age of patients was 49 to 70 years. Six trials included rituximab as the MT; three included Interferon alfa; other trials include thalidomide, lenalidomide, cyclophosphamide and prednisone, serine threonine kinase inhibitor enzastaurin, and mTOR inhibitor everolimus. MT did not improve OS compared to observation, OR 0.91, (95% CI 0.78‐1.07). Results were the same in a subgroup analysis by the type of maintenance (rituximab vs other). MT did decreased relapse rate, RR 0.76 (95% CI 0.65‐0.89) and improved disease control, OR 0.74 (95% CI 0.65‐0.84). Disease control was significantly improved in the subgroup of studies evaluating rituximab as maintenance OR 0.61 (95% CI 0.47‐0.79) and in the subgroup of R‐CHOP induction studies OR 0.77 (95% CI 0.67‐0.88). Serious or grade III/IV adverse events including neutropenia and infections were significantly more common in the maintenance arm, RR = 1.69 (95% CI 1.29‐2.22). MT in patients with DLBCL achieving CR or PR after induction therapy did not affect OS, yet it decreased relapse rate and improved disease control at the cost of higher infection rate. Our data do not support routine administration of MT in patients with DLBCL.     

Frequent downregulation of BTB and CNC homology 2 expression in Epstein–Barr virus‐positive diffuse large B‐cell lymphoma

Diffuse large B‐cell lymphoma (DLBCL) is the most common B‐cell lymphoma subtype, and the Epstein–Barr virus (EBV)‐positive subtype of DLBCL is known to show a more aggressive clinical behavior than the EBV‐negative one. BTB and CNC homology 2 (BACH2) has been highlighted as a tumor suppressor in hematopoietic malignancies; however, the role of BACH2 in EBV‐positive DLBCL is unclear. In the present study, BACH2 expression and its significance were studied in 23 EBV‐positive and 43 EBV‐negative patient samples. Immunohistochemistry revealed BACH2 downregulation in EBV‐positive cases (P < 0.0001), although biallelic deletion of BACH2 was not detected by FISH. Next, we analyzed the contribution of BACH2 negativity to aggressiveness in EBV‐positive B‐cell lymphomas using FL‐18 (EBV‐negative) and FL‐18‐EB cells (FL‐18 sister cell line, EBV‐positive). In BACH2‐transfected FL‐18‐EB cells, downregulation of phosphorylated transforming growth factor‐β‐activated kinase 1 (pTAK1) and suppression in p65 nuclear fractions were observed by Western blot analysis contrary to non‐transfected FL‐18‐EB cells. In patient samples, pTAK1 expression and significant nuclear p65, p50, and p52 localization were detected immunohistochemically in BACH2‐negative DLBCL (P < 0.0001, P = 0.006, and P = 0.001, respectively), suggesting that BACH2 downregulation contributes to constitutive activation of the nuclear factor‐κB pathway through TAK1 phosphorylation in BACH2‐negative DLBCL (most EBV‐positive cases). Although further molecular and pathological studies are warranted to clarify the detailed mechanisms, downregulation of BACH2 may contribute to constitutive activation of the nuclear factor‐κB pathway through TAK1 activation.     

Combination of CD47 and signal‐regulatory protein‐α constituting the “don’t eat me signal” is a prognostic factor in diffuse large B‐cell lymphoma

The interaction between CD47 and signal‐regulatory protein‐α (SIRPα) inhibits phagocytosis, thus affecting the clinical outcomes of neoplastic diseases. Although CD47 upregulation is associated with poor prognosis in several malignancies, the effect of SIRPα expression and its coexpression with CD47 remains unclear. This study aimed to investigate the clinicopathologic effect of CD47 and SIRPα expression in diffuse large B‐cell lymphoma (DLBCL). Immunostaining of 120 biopsy samples showed that CD47 is primarily expressed in tumor cells, whereas SIRPα is expressed in nonneoplastic stromal cells, mostly macrophages. CD47^high cases showed higher MYC protein expression and lower MYC translocation. The SIRPα^high cases presented significantly shorter overall survival (OS) and progression‐free survival (PFS) than SIRPα^low cases in the activated B‐cell (ABC) subtype of DLBCL (P = .04 and P = .02, respectively). Both CD47^high and SIRPα^high presented significantly shorter OS and PFS than other cases among all DLBCL patients (P = .01 and P = .004, respectively), and the ABC type (P = .04 and P = .008, respectively) but not the germinal center B‐cell type. Both CD47^high and SIRPα^high yielded a constant independent prognostic value for OS and PFS in multivariate analysis (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.20‐7.43; P = .02; and HR, 2.87; 95% CI, 1.42‐5.85; P = .003, respectively). To the best of our knowledge, this is the first study to report that combinatorial CD47 and SIRPα expression is a potential independent prognostic factor for DLBCL. Evaluation of CD47 and SIRPα expression could be useful before CD47 blockade therapy.     

The prognostic significance of EBV DNA load and EBER status in diagnostic specimens from diffuse large B‐cell lymphoma patients

Epstein–Barr virus (EBV)‐encoded small RNA in situ hybridization (EBER‐ISH) is a widely accepted method to evaluate EBV involvement in diffuse large B‐cell lymphoma (DLBCL), although little is known regarding associations between EBV DNA load and the EBER status and whether EBV DNA load data provide additional clinical information. In this study, we quantified EBV DNA load in diagnostic specimens from DLBCL patients diagnosed at our hospital to evaluate clinical implications of EBV DNA load in diagnostic specimens as contrasted with EBER‐ISH. Among 140 DLBCL patients without underlying immunodeficiency, 51 were evaluable for both EBER and EBV DNA load, 83 for EBER only and one for EBV DNA load only. The median EBV DNA load was 708 copies/µg. Although EBV DNA load was significantly higher for EBER‐positive patients than for EBER‐negative patients (p < 0.001), EBV DNA was detected in up to 72% of EBER‐negative patients. Progression‐free survival and overall survival were significantly worse for patients with EBV DNA load above 700 copies/µg than for those with EBV DNA load below 700 copies/µg (p = 0.009 and p = 0.003); they were also significantly worse for EBER‐positive patients than for EBER‐negative patients (p < 0.001 and p = 0.001). Even among EBER‐negative patients, higher EBV DNA load conferred worse progression‐free survival and overall survival (p = 0.041 and p = 0.013). These findings indicate that EBV DNA load in diagnostic specimens is not a simple surrogate for the EBER status and may be a potential biomarker associated with EBV involvement and prognosis in DLBCL. Copyright © 2015 John Wiley & Sons, Ltd.     

Treatment of Philadelphia‐negative myeloproliferative neoplasms in accelerated/blastic phase with azacytidine. Clinical results and identification of prognostic factors

There have been some reports on a possible role of azacytidine (AZA) in the treatment of accelerated/blastic phase evolved from Philadelphia‐negative myeloproliferative neoplasms (MPN‐AP/BP), but results are conflicting. In this study, we analyzed a cohort of 39 patients with MPN‐AP/BP treated frontline with AZA at the standard dosage (75 mg/m²). Median time from diagnosis to AP/BP evolution was 92.3 months (IR 29.9‐180.1). All patients were evaluable for hematologic response: two patients (5.2%) died early after AZA initiation, 13 patients (33.3%) had a progressive or stable disease, nine (23.1%) had a hematologic improvement (HI), seven (17.9%) achieved a partial response (PR), and eight (20.5%) a complete response (CR). Overall, 24 patients achieved a clinical hematologic response (HI + PR + CR), with an overall response rate of 61.5%. Median overall survival (OS) from AZA start of the whole cohort was 13.5 months (95% CI, 8.2‐18.7). There was no difference in median OS among patients with HI, PR, or CR (P = .908). These three subgroups as “responders” having been considered, a significantly better OS was observed in responder compared with nonresponder patients, with a median OS of 17.6 months (95% CI, 10.1‐25.0) versus 4.1 months (95% CI, 0.4‐10.0) (P = .001) Only female gender was significant for both achievement of response (.010) and OS duration (P = .002). In conclusion, AZA is useful for the management of MPN‐AP/BP, with an overall response rate (HI + PR + CR) of 61.5% and a longer OS in responders.     

Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non‐small cell lung cancer harboring activating EGFR mutations: Subgroup analysis of LUX‐Lung 3

In LUX‐Lung 3, afatinib significantly improved progression‐free survival (PFS) versus cisplatin/pemetrexed in EGFR mutation‐positive lung adenocarcinoma patients and overall survival (OS) in Del19 patients. Preplanned analyses in Japanese patients from LUX‐Lung 3 were performed. Patients were randomized 2:1 to afatinib or cisplatin/pemetrexed, stratified by mutation type (Del19/L858R/Other). Primary endpoint was PFS (independent review). Secondary endpoints included OS, objective response, and safety. Median PFS (data cut‐off: February 2012) for afatinib versus cisplatin/pemetrexed was 13.8 vs 6.9 months (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.20–0.70; P = 0.0014) in all Japanese patients (N = 83), with more pronounced improvements in those with common mutations (Del19/L858R; HR, 0.28; 95% CI, 0.15–0.52; P < 0.0001) and Del19 mutations (HR, 0.16; 95% CI, 0.06–0.39; P < 0.0001). PFS was also improved in L858R patients (HR, 0.50; 95% CI, 0.20–1.25; P = 0.1309). Median OS (data cut‐off: November 2013) with afatinib versus cisplatin/pemetrexed was 46.9 vs 35.8 months (HR, 0.75; 95% CI, 0.40–1.43; P = 0.3791) in all Japanese patients, with greater benefit in patients with common mutations (HR, 0.57; 95% CI, 0.29–1.12; P = 0.0966) and Del19 mutations (HR, 0.34; 95% CI, 0.13–0.87; P = 0.0181); OS was not significantly different in L858R patients (HR, 1.13; 95% CI, 0.40–3.21; P = 0.8212). Following study treatment discontinuation, most patients (93.5%) received subsequent anticancer therapy. The most common treatment‐related adverse events were diarrhea, rash/acne, nail effects and stomatitis with afatinib and nausea, decreased appetite, neutropenia, and leukopenia with cisplatin/pemetrexed. Afatinib significantly improved PFS versus cisplatin/pemetrexed in Japanese EGFR mutation‐positive lung adenocarcinoma patients and OS in Del19 but not L858R patients ( www.clinicaltrials.gov ; NCT00949650).     

Epstein–Barr virus presence in pediatric diffuse large B‐cell lymphoma reveals a particular association and latency patterns: Analysis of viral role in tumor microenvironment

Non‐Hodgkin's lymphoma represents 6–10% of pediatric malignancies, and diffuse large B‐cell lymphoma (DLBCL) is one of the three major subtypes. The 2008 WHO classification included a new entity, Epstein–Barr virus (EBV)‐positive DLBCL of the elderly, affecting patients >50 years. It has been demonstrated that EBV may play a role in tumor microenvironment composition, disturbing antitumor immune response and disease progression. As most studies were performed in adults, our aim was to assess EBV presence and latency pattern, as well as T‐cell microenvironment in a pediatric DLBCL series of Argentina. The study was conducted on formalin‐fixed paraffin‐embedded biopsies from 25 DLBCL patients. EBV‐encoded small nuclear early regions (EBERs) expression was performed by in situ hybridization, whereas EBV gene expression was analyzed using real‐time PCR. Epstein–Barr virus latent membrane proteins (LMP)1, LMP2A, CD3, CD4, CD8 and Foxp3 expression were assessed by immunohistochemistry (IHC). Forty percent of cases showed EBV expression, with a significantly higher incidence among patients <10 years (p = 0.018), and with immunosuppressed (p = 0.023). T‐cell subsets were not altered by EBV presence. Full EBV latency antigen expression (latency type III) was the most frequently pattern observed, together with BZLF1 lytic gene expression. One patient showed II‐like pattern (LMP1 without LMP2A expression). Based exclusively on IHC, some patients showed latency II/III (EBERs and LMP1 expression) or I (EBERs only). These findings suggest that EBV association in our series was higher than the previously demonstrated for elderly DLBCL and that EBV latency pattern could be more complex from those previously observed. Therefore, EBV could be an important cofactor in pediatric DLBCL lymphomagenesis.     

The therapeutic effect of rituximab on CD5‐positive and CD5‐negative diffuse large B‐cell lymphoma

The prognosis of diffuse large B‐cell lymphoma (DLBCL) has improved markedly in recent years of rituximab era. The prognosis of de novo CD5‐positive DLBCL is reported to be poor, but the effect of rituximab on this type of lymphoma remains unclear. To investigate the effect of rituximab on CD5‐positive DLBCL, we collected DLBCL patients and analysed prognostic factors. A total of 157 patients with DLBCL who were immunophenotyped with flow‐cytometry (FCM) and treated with chemotherapy were subjected to analysis. Those treated with radiotherapy alone or with supportive therapy only were not included. Patients diagnosed in 2003 or later were treated with rituximab combined chemotherapy. There were 95 males and 62 females. Their age ranged from 20 to 91 years old, and the median was 65 years. Nineteen patients were diagnosed as having de novo CD5‐positive DLBCL. Rituximab was given alongside chemotherapy in 85 patients. Of these, 11 were positive for CD5 and 74 were negative. The addition of rituximab improved the overall survival (OS) of DLBCL patients (2‐year OS: 82% vs. 70%, p = 0.01). For CD5‐negative DLBCL, patients treated with rituximab showed 2‐year OS of 84%, which was significantly better than those treated without rituximab (70%, p = 0.008). However, for CD5‐positive DLBCL, the prognosis was not statistically different between the patients treated with and without rituximab (59% vs. 50%, p = 0.72). Although rituximab improved the prognosis of DLBCL, such improvement was restricted to the CD5‐negative group. Further investigation is required to improve the prognosis of patients with CD5‐positive DLBCL. Copyright © 2009 John Wiley & Sons, Ltd.     

Clinicopathological prognostic indicators in 107 patients with diffuse large B‐cell lymphoma transformed from follicular lymphoma

Follicular lymphoma (FL) frequently transforms into diffuse large B‐cell lymphoma (DLBCL). To clarify the associated clinicopathological prognostic parameters, we examined the correlation of 11 histopathological parameters with progression‐free survival (PFS) and overall survival (OS) in 107 consecutive patients who had DLBCL with pre‐existing (asynchronous) or synchronous FL. The patients comprised 58 men and 49 women with a median age of 56 years. For DLBCL, the complete response rate was 81%, overall response rate was 88%, and 5‐year PFS and OS rates were 55% and 79%, respectively. Immunohistochemical analysis of the DLBCL component revealed the following positivity rates: CD10, 64%; Bcl‐2, 83%; Bcl‐6, 88%; MUM1, 42%; GCB, 82%; cMyc index ≥80%, 17%; and Ki‐67 index ≥90%, 19%. IGH/BCL2 fusion was positive in 57% of DLBCL cases. In univariate analyses, asynchronous FL and DLBCL (24%, P = 0.021), 100% proportion of DLBCL (29%, P = 0.004), Bcl‐2 positivity (P = 0.04), and high Ki‐67 index (P = 0.003) were significantly correlated with shorter PFS. Asynchronous FL and DLBCL (P = 0.003), 100% proportion of DLBCL (P = 0.001), and high Ki‐67 index (P = 0.004) were significantly correlated with shorter OS. In a multivariate analysis, asynchronous FL and DLBCL (P = 0.035) and 100% proportion of DLBCL (P = 0.016) were significantly correlated with shorter OS. Thus, asynchronism and 100% proportion of DLBCL, that is, FL relapsed as pure DLBCL, or FL and DLBCL at different sites, were significant predictors of unfavorable outcome of patients with DLBCL transformed from FL.     

Relapse in stage I(E) diffuse large B‐cell lymphoma

Despite a general favourable outcome in limited stage diffuse large B‐cell lymphoma (DLBCL), relapses occur in about 10 to 20% of patients. Prognostic models only partially identify patients at risk for relapse. Moreover, it is not known whether the outcome after such a relapse is similar to the outcome after relapse in advanced stages. From January 2004 through December 2012, all newly diagnosed patients with stage I(E) DLBCL were retrospectively analysed from 2 clinical databases to investigate the relapse pattern and outcome in relation to initial treatment and clinical characteristics. In 126 patients (median age 64 years), histologically confirmed stage I(E) DLBCL was diagnosed. With a median follow‐up of 53 months (range 5‐132 months), 1 progressive disease and 18 relapses occurred. The 5‐year time to tumour progression and disease‐specific survival were 85% (95% CI 79‐91%) and 92% (95% CI 87%‐97%), respectively. We observed no significant difference in relapse localization, time to tumour progression, and disease‐specific survival between patients treated with abbreviated R‐CHOP plus involved field radiotherapy or with 6 to 8 cycles of R‐CHOP. Analysis of relapses showed relapse >5 years after initial treatment (late relapse) in 5 of 19 patients (26%). Six of 19 patients (32%) had central nervous system relapse. Three of 11 relapsed cases available for analysis (28%) showed an MYC translocation, suggesting an overrepresentation in the relapse group. Outcome of patients with a relapse was poor with a median survival after relapse of 8 months. Only 1 patient (5%) underwent successful autologous stem cell transplantation. To improve outcome in these patients, early identification of new biological factors such as a MYC translocation or a high risk for CNS dissemination might be helpful. Moreover, treatment of any relapse after stage I disease should be taken seriously. Salvage treatment should be similar to relapses after advanced DLBCL.     

Bcl‐2, Bcl‐6, and the International Prognostic Index are prognostic indicators in patients with diffuse large B‐cell lymphoma treated with rituximab‐containing chemotherapy

This study aimed to clarify the clinicopathological prognostic parameters of de novo diffuse large B‐cell lymphoma (DLBCL) in the rituximab era. We examined the correlation of 22 clinicopathological parameters with progression‐free survival (PFS), overall survival (OS), and primary refractory disease in 285 DLBCL patients treated with rituximab‐containing chemotherapy. Complete response rate was 87%, overall response rate was 91%, 5‐year PFS rate was 72%, and 5‐year OS rate was 91%. By log–rank test, higher International Prognostic Index (IPI) (P < 0.0001), Bcl‐2 positivity (P = 0.0013), Bcl‐6 negativity (P = 0.0112), and no irradiation (P = 0.0371) were significantly correlated with shorter PFS; higher IPI (P = 0.0107), starry sky pattern (P = 0.0466), and no irradiation (P = 0.0264) correlated with shorter OS. In multivariate analyses, higher IPI (P = 0.0006), Bcl‐2 positivity (P = 0.0015), and Bcl‐6 negativity (P = 0.04) were significantly correlated with shorter PFS; higher IPI (P = 0.0045) correlated with shorter OS. Bcl‐2 (P = 0.0029), Bcl‐6 (P = 0.002), and IPI (P < 0.0001) were significantly correlated with primary refractory disease. In conclusion, Bcl‐2 positivity, Bcl‐6 negativity, and higher IPI were indicators of shorter PFS and OS plus primary refractory disease in patients with DLBCL in the rituximab era.     

Hematopoietic stem cell transplantation for diffuse large B‐cell lymphoma having 8q24/MYC rearrangement in Japan

The prognosis of diffuse large B‐cell lymphoma (DLBCL) having MYC rearrangement (MYC‐R), including double hit lymphoma (DHL), is poor by standard immunochemotherapy. To evaluate the significance of hematopoietic stem cell transplantation (SCT) for DLBCL with MYC‐R, we retrospectively analyzed Japanese SCT registry data. In total, 54 patients with DLBCL with MYC‐R were identified from 4336 registered adult DLBCL patients. Detailed clinical and cytogenetic information was obtained for 48 patients. The median age at diagnosis of the 48 patients was 54.5 (range 21–67) years. Twenty‐six (54%) patients had MYC‐R only (single hit), and 22 (46%) had MYC‐R and BCL2, and/or BCL6 rearrangement (double/triple hit). In 12 patients who received auto‐SCT during the first complete response (CR), both the 2‐year overall survival (OS) and progression‐free survival (PFS) rates were 75.0% (95% confidence interval [CI], 40.8%–91.2%). In 20 patients who received auto‐SCT after relapsed or refractory state, the 2‐year OS and PFS rates were 68.2% (95% CI, 41.9%–84.5%) and 59.6% (95% CI, 35.1%–77.4%), respectively. In 17 patients who received allo‐SCT, only 4 patients underwent SCT in CR. The 2‐year OS and PFS rates were 29.4% (95% CI, 10.7%–51.1%) and 17.6% (95% CI, 4.3%–38.3%), respectively. The rate of non‐relapse mortality at 1 year was 41.2% (95% CI, 17.1%–64.0%) in this group. The outcomes of single hit and double or triple hit were not different. These findings suggest that auto‐SCT may be effective for MYC‐R DLBCL, including DHL patients of chemosensitive relapsed or refractory state. Since most patients received allo‐SCT not in CR, the outcome of allo‐SCT was unsatisfactory due to high non‐relapse mortality and early relapse. To clarify the role of allo‐SCT for MYC‐R DLBCL, further accumulation of patients is necessary.