Humoral Immunity After COVID-19 Vaccination in Chronic Lymphocytic Leukemia and Other Indolent Lymphomas: A Single-Center Observational Study.

BACKGROUND: Chronic lymphocytic leukemia (CLL) and other non-Hodgkin's lymphomas (NHLs) lead to broad immunosuppression, conferring a greater risk for morbidity and mortality from SARS-CoV-2. Our study analyzed antibody (Ab) seropositivity from SARS-CoV-2 vaccination in patients with these cancers. METHODS: In the final analysis, 240 patients were involved, and seropositivity was defined as a positive total or spike protein Ab. RESULTS: Seropositivity was 50% in CLL, 68% in WM, and 70% in the remaining NHLs. Moderna vaccination led to higher seropositivity compared to Pfizer vaccination across all cancers (64% vs. 49%; P = .022) and specifically CLL patients (59% vs. 43%; P = .029). This difference was not explainable by differences in treatment status or prior anti-CD20 monoclonal Ab therapy. In CLL patients, current or prior cancer therapy led to lower seropositivity compared to treatment-naïve patients (36% vs. 68%; P = .000019). CLL patients treated with Bruton's tyrosine kinase (BTK) inhibitors had better seropositivity after receiving the Moderna vaccination compared to Pfizer (50% vs. 23%; P = .015). Across all cancers, anti-CD20 agents within 1 year led to a lower Ab response compared to greater than one year (13% vs. 40%; P = .022), a difference which persisted after booster vaccination. CONCLUSION: Antibody response is lower in patients with indolent lymphomas compared to the general population. Lower Ab seropositivity was found in patients with a history of anti-leukemic agent therapy or those immunized with Pfizer vaccine. This data suggests that Moderna vaccination may confer a greater degree of immunity against SARS-CoV-2 in patients with indolent lymphomas.

Pembrolizumab followed by AVD in untreated early unfavorable and advanced-stage classical Hodgkin lymphoma.

Pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 protein, has demonstrated efficacy in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the complete metabolic response (CMR) rate and safety of pembrolizumab monotherapy in newly diagnosed cHL, we conducted a multicenter, single-arm, phase 2 investigator-initiated trial of sequential pembrolizumab and doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy. Patients ≥18 years of age with untreated, early, unfavorable, or advanced-stage disease were eligible for treatment. Thirty patients (early unfavorable stage, n = 12; advanced stage, n = 18) were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4 to 6 cycles, depending on stage and bulk. Twelve had either large mediastinal masses or bulky disease (>10 cm). After pembrolizumab monotherapy, 11 patients (37%) demonstrated CMRs, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography computed tomography scans had >90% reduction in metabolic tumor volume. All patients achieved CMR after 2 cycles of AVD and maintained their responses at the end of treatment. With a median follow-up of 22.5 months (range, 14.2-30.6) there were no changes in therapy, progressions, or deaths. No patients received consolidation radiotherapy, including those with bulky disease. Therapy was well tolerated. The most common immune-related adverse events were grade 1 rash (n = 6) and grade 2 infusion reactions (n = 4). One patient had reversible grade 4 transaminitis and a second had reversible Bell's palsy. Brief pembrolizumab monotherapy followed by AVD was both highly effective and safe in patients with newly diagnosed cHL, including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.

Health-related quality of life in early-stage Hodgkin lymphoma: a longitudinal analysis of the ABVD arm in the randomized controlled trial HD.6.

Early-stage Hodgkin lymphoma has become one of the most curable hematologic malignancies. Depending upon the disease location, possible toxicities, and patient preference, chemotherapy alone with ABVD remains an accepted treatment modality for this disease. There remains a paucity of data regarding the longitudinal trajectory of health-related quality of life (HRQoL) in patients treated for HL. The impact of disease and treatment on HRQoL is increasingly important to understand as the number of long-term survivors increases. We report the longitudinal HRQoL using data prospectively collected from diagnosis up to 10 years post-treatment in the ABVD arm of the HD.6 randomized controlled trial for early-stage HL patients (N=169). We analyzed HRQoL using the EORTC QLQ-C30 collected at baseline, 3 months, 6 months, and 12 months after completion of chemotherapy and yearly up to year 10. Clinically and statistically significant improvements were noted for specific domains including emotional (3 months post-treatment), social (12 months post-treatment) and financial functioning (2 years post-treatment), and the specific symptom of fatigue (6 months post-treatment) during the follow-up period. To our knowledge, this is the first prospective, longitudinal analysis of HRQoL specifically among patients with early-stage HL treated with ABVD therapy alone. Although improvements were noted, sustained clinically and statistically significant improvements were noted only in select symptoms emphasizing the need to better understand and optimize HRQoL among this patient group.

NCCN Guidelines® Insights: Hodgkin Lymphoma, Version 2.2022.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte-predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

Hodgkin Lymphoma, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

PD-1/PD-L1 expression and interaction by automated quantitative immunofluorescent analysis show adverse prognostic impact in patients with diffuse large B-cell lymphoma having T-cell infiltration: a study from the International DLBCL Consortium Program.

Programmed cell death protein 1/programmed cell death protein ligand1 (PD-1/PD-L1) interaction is an important immune checkpoint targeted by anti-PD-1/PD-L1 immunotherapies. However, the observed prognostic significance of PD-1/PD-L1 expression in diffuse large B-cell lymphoma treated with the standard of care has been inconsistent and even contradictory. To clarify the prognostic role of PD-1/PD-L1 expression and interaction in diffuse large B-cell lymphoma, in this study we used 3-marker fluorescent multiplex immunohistochemistry and Automated Quantitative Analysis Technology to assess the CD3+, PD-L1+, and PD-1+CD3+ expression in diagnostic samples and PD-1/PD-L1 interaction as indicated by presence of PD-1+CD3+ cells in the vicinity of PD-L1+ cells, analyzed their prognostic effects in 414 patients with de novo diffuse large B-cell lymphoma, and examined whether PD-1/PD-L1 interaction is required for the prognostic role of PD-1+/PD-L1+ expression. We found that low T-cell tissue cellularity, tissue PD-L1+ expression (irrespective of cell types), PD-1+CD3+ expression, and PD-1/PD-L1 interaction showed hierarchical adverse prognostic effects in the study cohort. PD-1/PD-L1 interaction showed higher sensitivity and specificity than PD-1+ and PD-L1+ expression in predicting inferior prognosis in patients with high CD3+ tissue cellularity ("hot"/inflammatory tumors). However, both PD-1+ and PD-L1+ expression showed adverse prognostic effects independent of PD-1/PD-L1 interaction, and PD-1/PD-L1 interaction showed favorable prognostic effect in PD-L1+ patients without high CD3+ tissue cellularity. Macrophage function and tumor-cell MYC expression may contribute to the PD-1-independent adverse prognostic effect of PD-L1+ expression. In summary, low T-cell tissue cellularity has unfavorable prognostic impact in diffuse large B-cell lymphoma, and tissue PD-L1+ expression and T-cell-derived PD-1+ expression have significant adverse impact only in patients with high T-cell infiltration. PD-1/PD-L1 interaction in tissue is essential but not always responsible for the inhibitory effect of PD-L1+/PD-1+ expression. These results suggest the benefit of PD-1/PD-L1 blockade therapies only in patients with sufficient T-cell infiltration, and the potential of immunofluorescent assays and Automated Quantitative Analysis in the clinical assessment of PD-1/PD-L1 expression and interaction.

Controversies in the Approach to Initial Therapy of Hodgkin Lymphoma.

PURPOSE OF REVIEW: Availability of highly effective novel agents has altered the approach to initial therapy in patients with classical Hodgkin lymphoma (cHL). We will review controversies in the following areas: (1) the role of radiation in early unfavorable disease and the optimal treatment strategies for (2) advanced-stage disease and (3) elderly patients. RECENT FINDINGS: Strategies incorporating brentuximab vedotin into frontline treatment of cHL yielded favorable results in non-randomized elderly studies and were compared to ABVD in advanced disease among adults. Meanwhile, four cycles of escalated BEACOPP yielded unprecedented favorable results for the treatment of advanced disease in the German Hodgkin Study Group 18 study. The addition of novel agents to conventional treatment strategies has the potential to improve outcomes in high-risk groups of patients while reducing toxicity. The role of radiation therapy remains in question but may see diminished use with the incorporation of more effective agents in the frontline setting.

Assessment of CD37 B-cell antigen and cell of origin significantly improves risk prediction in diffuse large B-cell lymphoma.

CD37 (tetraspanin TSPAN26) is a B-cell surface antigen widely expressed on mature B cells. CD37 is involved in immune regulation and tumor suppression but its function has not been fully elucidated. We assessed CD37 expression in de novo diffuse large B-cell lymphoma (DLBCL), and investigated its clinical and biologic significance in 773 patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 231 patients treated with CHOP. We found that CD37 loss (CD37-) in ∼60% of DLBCL patients showed significantly decreased survival after R-CHOP treatment, independent of the International Prognostic Index (IPI), germinal center B-cell-like (GCB)/activated B-cell-like (ABC) cell of origin, nodal/extranodal primary origin, and the prognostic factors associated with CD37-, including TP53 mutation, NF-κBhigh, Mychigh, phosphorylated STAT3high, survivinhigh, p63-, and BCL6 translocation. CD37 positivity predicted superior survival, abolishing the prognostic impact of high IPI and above biomarkers in GCB-DLBCL but not in ABC-DLBCL. Combining risk scores for CD37- status and ABC cell of origin with the IPI, defined as molecularly adjusted IPI for R-CHOP (M-IPI-R), or IPI plus immunohistochemistry (IHC; IPI+IHC) for CD37, Myc, and Bcl-2, significantly improved risk prediction over IPI alone. Gene expression profiling suggested that decreased CD20 and increased PD-1 levels in CD37- DLBCL, ICOSLG upregulation in CD37+ GCB-DLBCL, and CD37 functions during R-CHOP treatment underlie the pivotal role of CD37 status in clinical outcomes. In conclusion, CD37 is a critical determinant of R-CHOP outcome in DLBCL especially in GCB-DLBCL, representing its importance for optimal rituximab action and sustained immune responses. The combined molecular and clinical prognostic indices, M-IPI-R and IPI+IHC, have remarkable predictive values in R-CHOP-treated DLBCL.

NCCN Guidelines Insights: Hodgkin Lymphoma, Version 1.2018.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL.

Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression.

Several non-Hodgkin lymphoma (NHL) subtypes, including diffuse large B-cell lymphoma (DLBCL), variably express CD30. This phase 2, open-label study evaluated the efficacy of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, in relapsed/refractory CD30(+) NHL. This planned subset analysis of B-cell NHLs includes 49 patients with DLBCL and 19 with other B-cell NHLs. Objective response rate was 44% for DLBCL, including 8 (17%) complete remissions (CRs) with a median duration of 16.6 months thus far (range, 2.7 to 22.7+ months). There was no statistical correlation between response and level of CD30 expression; however, all responding patients had quantifiable CD30 by computer-assisted assessment of immunohistochemistry. DLBCL patients were generally refractory to first-line (76%) and most recent therapies (82%), and 44% of these refractory patients responded (15% CRs). Patients with other B-cell lymphomas also responded: 1 CR, 2 partial responses (PRs) of 6 with gray zone, 1 CR of 6 with primary mediastinal B-cell, and 1 CR of 3 with posttransplant lymphoproliferative disorder. Adverse events were consistent with known toxicities. The combination of brentuximab vedotin with rituximab was generally well tolerated and had activity similar to brentuximab vedotin alone. Overall, significant activity with brentuximab vedotin was observed in relapsed/refractory DLBCL, and responses occurred across a range of CD30 expression. This study was registered at www.clinicaltrials.gov as #NCT01421667.

Hodgkin Lymphoma Version 1.2017, NCCN Clinical Practice Guidelines in Oncology.

This portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects.

Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: subset analysis of randomized trial intergroup SWOG S9704.

Double hit lymphoma (DHL) and double protein-expressing (MYC, BCL2) lymphomas (DPL) fare poorly with R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisolone); consolidative autologous stem cell transplant (ASCT) may improve outcomes. S9704, a phase III randomized study of CHOP +/-R with or without ASCT enabled evaluation of intensive consolidation. Immunohistochemistry (IHC) identified 27 of 198 patients (13·6%) with MYC overexpression; 20 (74%) harboured concurrent BCL2 overexpression. Four had DHL and 16 had DPL only. With median 127 months follow-up, there is a trend favouring outcomes after ASCT in DPL and MYC protein overexpressing patients, whereas all DHL patients have died irrespective of ASCT.

Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma.

BACKGROUND: The efficacy of autologous stem-cell transplantation during the first remission in patients with diffuse, aggressive non-Hodgkin's lymphoma classified as high-intermediate risk or high risk on the International Prognostic Index remains controversial and is untested in the rituximab era. METHODS: We treated 397 patients who had disease with an age-adjusted classification of high risk or high-intermediate risk with five cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus rituximab. Patients with a response were randomly assigned to receive three additional cycles of induction chemotherapy (control group) or one additional cycle of induction chemotherapy followed by autologous stem-cell transplantation (transplantation group). The primary efficacy end points were 2-year progression-free survival and overall survival. RESULTS: Of 370 induction-eligible patients, 253 were randomly assigned to the transplantation group (125) or the control group (128). Forty-six patients in the transplantation group and 68 in the control group had disease progression or died, with 2-year progression-free survival rates of 69 and 55%, respectively (hazard ratio in the control group vs. the transplantation group, 1.72; 95% confidence interval [CI], 1.18 to 2.51; P=0.005). Thirty-seven patients in the transplantation group and 47 in the control group died, with 2-year overall survival rates of 74 and 71%, respectively (hazard ratio, 1.26; 95% CI, 0.82 to 1.94; P=0.30). Exploratory analyses showed a differential treatment effect according to risk level for both progression-free survival (P=0.04 for interaction) and overall survival (P=0.01 for interaction). Among high-risk patients, the 2-year overall survival rate was 82% in the transplantation group and 64% in the control group. CONCLUSIONS: Early autologous stem-cell transplantation improved progression-free survival among patients with high-intermediate-risk or high-risk disease who had a response to induction therapy. Overall survival after transplantation was not improved, probably because of the effectiveness of salvage transplantation. (Funded by the National Cancer Institute, Department of Health and Human Services, and others; SWOG-9704 ClinicalTrials.gov number, NCT00004031.).

An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era.

The International Prognostic Index (IPI) has been the basis for determining prognosis in patients with aggressive non-Hodgkin lymphoma (NHL) for the past 20 years. Using raw clinical data from the National Comprehensive Cancer Network (NCCN) database collected during the rituximab era, we built an enhanced IPI with the goal of improving risk stratification. Clinical features from 1650 adults with de novo diffuse large B-cell lymphoma (DLBCL) diagnosed from 2000-2010 at 7 NCCN cancer centers were assessed for their prognostic significance, with statistical efforts to further refine the categorization of age and normalized LDH. Five predictors (age, lactate dehydrogenase (LDH), sites of involvement, Ann Arbor stage, ECOG performance status) were identified and a maximum of 8 points assigned. Four risk groups were formed: low (0-1), low-intermediate (2-3), high-intermediate (4-5), and high (6-8). Compared with the IPI, the NCCN-IPI better discriminated low- and high-risk subgroups (5-year overall survival [OS]: 96% vs 33%) than the IPI (5 year OS: 90% vs 54%), respectively. When validated using an independent cohort from the British Columbia Cancer Agency (n = 1138), it also demonstrated enhanced discrimination for both low- and high-risk patients. The NCCN-IPI is easy to apply and more powerful than the IPI for predicting survival in the rituximab era.

High Body Mass Index in Elderly Patients With DLBCL Treated With Rituximab-Containing Therapy Compensates for Negative Impact of Male Sex.

BACKGROUND: The impact of patient body habitus and sex on outcomes in diffuse large B-cell lymphoma (DLBCL) remains controversial. We investigated the impact of body mass index (BMI), body surface area (BSA), age, and sex on clinical outcomes in patients with DLBCL treated in the rituximab era. PATIENTS AND METHODS: Patients with de novo DLBCL (n=1,386) diagnosed between June 2000 and December 2010 treated with rituximab-containing chemotherapy were identified from the NCCN Oncology Outcomes Database for Non-Hodgkin's Lymphoma. Progression-free survival (PFS) and overall survival (OS) at 3 years were analyzed based on sex, age, and baseline BMI/BSA. RESULTS: High BMI was associated with a lower risk of disease progression or death than low or normal BMI, whereas male sex was associated with poor clinical outcomes, especially among elderly patients (age >60 years). Compared with elderly women, elderly men experienced worse PFS (3-year hazard ratio [HR], 1.5) and OS (3-year HR, 1.6), but these differences diminished with increases in BMI and BSA. In multivariable analysis, normal BMI compared with high BMI was independently associated with poor outcomes (3-year PFS HR, 1.5; OS HR, 1.6) after adjusting for sex. Notably, only 13% of elderly men had BMI less than 25 kg/m2 and only 26% had BSA less than 2 m2 CONCLUSIONS: Analysis of unselected patients with DLBCL treated with rituximab-containing chemotherapy confirmed an age-dependent disadvantage to male sex in treatment outcomes, but this effect is abrogated by higher levels of BMI and BSA in most North American men.

Cutaneous Involvement in a Case of Intravascular T-Cell Lymphoma With a γδ Phenotype.

Intravascular lymphomas (IVL) are uncommon variants of extranodal non-Hodgkin which are usually difficult to diagnose because of their lack of clinical uniformity. Most cases are of B-cell differentiation followed by natural killer/T-cell differentiation and underlying CD30 lymphoproliferative conditions. Epstein-Barr virus is pathogenically related in most of the natural killer/T-cell variants, and the skin is a common site of presentation noted in approximately 40% of cases. Recently, cases with uncommon phenotypes have been described, expanding our understanding of the pathogenesis of this condition. In this report, we describe a 67-year-old man with a 3-month history of constitutional symptoms associated with linear purpuric macules on the trunk, pancytopenia, and high levels of serum lactate dehydrogenase. He had been followed for longstanding adenopathy and hepatosplenomegaly. Skin biopsy demonstrated a intravascular lymphocytic proliferation with positivity for CD3, CD2, CD5, and γδ T-cell receptor marker; in situ hybridization Epstein-Barr virus RNA was negative. The patient was subsequently treated with chemotherapy and allogenic stem cell transplant. He remains in complete remission 6 months posttransplant. Although the presence of hepatosplenomegaly led to consideration of a hepatosplenic T-cell lymphoma, it was pre-existing for several years making the diagnosis doubtful. To our knowledge, this is the first case report of an IVL γδ T-cell lymphoma.

ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma.

BACKGROUND: Chemotherapy plus radiation treatment is effective in controlling stage IA or IIA nonbulky Hodgkin's lymphoma in 90% of patients but is associated with late treatment-related deaths. Chemotherapy alone may improve survival because it is associated with fewer late deaths. METHODS: We randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin's lymphoma to treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone or to treatment with subtotal nodal radiation therapy, with or without ABVD therapy. Patients in the ABVD-only group, both those with a favorable risk profile and those with an unfavorable risk profile, received four to six cycles of ABVD. Among those assigned to subtotal nodal radiation therapy, patients who had a favorable risk profile received subtotal nodal radiation therapy alone and patients with an unfavorable risk profile received two cycles of ABVD plus subtotal nodal radiation therapy. The primary end point was 12-year overall survival. RESULTS: The median length of follow-up was 11.3 years. At 12 years, the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal radiation therapy (hazard ratio for death with ABVD alone, 0.50; 95% confidence interval [CI], 0.25 to 0.99; P=0.04); the rates of freedom from disease progression were 87% and 92% in the two groups, respectively (hazard ratio for disease progression, 1.91; 95% CI, 0.99 to 3.69; P=0.05); and the rates of event-free survival were 85% and 80%, respectively (hazard ratio for event, 0.88; 95% CI, 0.54 to 1.43; P=0.60). Among the patients randomly assigned to ABVD alone, 6 patients died from Hodgkin's lymphoma or an early treatment complication and 6 died from another cause; among those receiving radiation therapy, 4 deaths were related to Hodgkin's lymphoma or early toxic effects from the treatment and 20 were related to another cause. CONCLUSIONS: Among patients with Hodgkin's lymphoma, ABVD therapy alone, as compared with treatment that included subtotal nodal radiation therapy, was associated with a higher rate of overall survival owing to a lower rate of death from other causes. (Funded by the Canadian Cancer Society and the National Cancer Institute; HD.6 ClinicalTrials.gov number, NCT00002561.).

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP.

MYC dysregulation, including MYC gene rearrangement and Myc protein overexpression, is of increasing clinical importance in diffuse large B-cell lymphoma (DLBCL). However, the roles of MYC and the relative importance of rearrangement vs overexpression remain to be refined. Gaining knowledge about the tumor biology associated with MYC dysregulation is important to understand the roles of MYC and MYC-associated biology in lymphomagenesis. In this study, we determined MYC rearrangement status (n=344) and Myc expression (n=535) in a well-characterized DLBCL cohort, individually assessed the clinical and pathobiological features of patients with MYC rearrangement and Myc protein overexpression, and analyzed the prognosis and gene expression profiling signatures associated with these MYC abnormalities in germinal center B-cell-like and activated B-cell-like DLBCL. Our results showed that the prognostic importance of MYC rearrangement vs Myc overexpression is significantly different in germinal center B-cell-like vs activated B-cell-like DLBCL. In germinal center B-cell-like DLBCL, MYC-rearranged germinal center B-cell-like DLBCL patients with Myc overexpression significantly contributed to the clinical, biological, and prognostic characteristics of the overall Myc-overexpressing germinal center B-cell-like DLBCL group. In contrast, in activated B-cell-like DLBCL, the occurrence, clinical and biological features, and prognosis of Myc overexpression were independent of MYC rearrangement. High Myc levels and Myc-independent mechanisms, either tumor cell intrinsic or related to tumor microenvironment, conferred significantly worse survival to MYC-rearranged germinal center B-cell-like DLBCL patients, even among Myc(high)Bcl-2(high) DLBCL patients. This study provides new insight into the tumor biology and prognostic effects associated with MYC dysregulation and suggest that detection of both MYC translocations and evaluation of Myc and Bcl-2 expression is necessary to predict the prognosis of DLBCL patients.

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy.

Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in a variety of human neoplasms. The prognostic significance of survivin expression in diffuse large B-cell lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is unclear. We used standard immunohistochemistry methods to quantify survivin expression in 463 patients with de novo diffuse large B-cell lymphoma who received the R-CHOP. Of the 463 patients, 269 (58%) had survivin overexpression with a cutoff of >25%, associated with an International Prognostic Index score of >2 (P=0.015), disease in ≥2 extranodal sites (P=0.011), and a high Ki-67 index (P<0.0001). Among patients with activated B cell-like disease, the overall survival rate of survivin-positive patients was significantly lower than that of survivin-negative patients (P=0.033); multivariate analysis confirmed that in these patients, survivin overexpression was an independent prognostic factor for survival. Among patients with wild-type p53 overexpression, the overall survival and progression-free survival rates of the survivin-positive group were significantly lower than those of the survivin-negative group (P=0.035 and P=0.04 respectively). In STAT3-positive patients, survivin overexpression was associated with significantly better survival. Among patients with activated B cell-like disease, survivin-positive compared with survivin-negative groups had significantly different gene expression signatures, including genes involved in mitosis or tumor cell proliferation. Our results indicate that survivin is an independent prognostic factor for poor outcome in patients with activated B cell-like disease treated with the R-CHOP regimen, and patients with survivin-positive activated B cell-like diffuse large B-cell lymphoma seem to benefit less from this treatment and may require additional novel agents.