Surgical Management and Long-Term Outcomes of BIA-ALCL: A Multidisciplinary Approach.

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a subtype of ALCL that arises as a seroma or a mass in the capsule surrounding textured breast implants. However, collections of cases usually come from large groups of institutions or countries, with different approaches regarding surgery and treatment. Here we describe a cohort of 18 cases undergoing implant removal and capsulectomy followed at Memorial Sloan Kettering Cancer Center (MSKCC). PATIENTS AND METHODS: We retrospectively analyzed all the cases of women with breast implants undergoing implant removal and capsulectomy for BIA-ALCL at MSKCC from January 2011 to June 2020. RESULTS: Median age at diagnosis was 57 (range 35-77) years following a median implant exposure of 11 (range 7-33) years. All known implants were macrotextured with the proprietary Biocell macrotexturing pattern from salt-loss technique. A total of 16 patients (89%) had implants placed for breast cancer reconstruction. Patients presented with clinically evident effusion in 78% of cases and a mass in 17% of cases, and 83% of patients presented with stage 1 BIA-ALCL. Patients were followed for a median of 43.4 months (SD 45 months) after diagnosis. There were no cases of recurrent ALCL. All patients remain disease free and no patients died of ALCL. CONCLUSIONS: In this cohort of patients with BIA-ALCL surgically treated and followed at a single institution, we confirm the importance of adequate surgery (bilateral implant removal and complete capsulectomy) in patients presenting with seroma-confined disease. This dataset reinforces high rates of progression-free and overall survival when diagnosis is identified and treatment performed in those with limited-stage disease.

Comparative effectiveness of ZUMA-5 (axi-cel) vs SCHOLAR-5 external control in relapsed/refractory follicular lymphoma.

In the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients. Here, outcomes from ZUMA-5 are compared with the international SCHOLAR-5 cohort, which applied key ZUMA-5 trial eligibility criteria simulating randomized controlled trial conditions. SCHOLAR-5 data were extracted from institutions in 5 countries, and from 1 historical clinical trial, for r/r FL patients who initiated a third or higher line of therapy after July 2014. Patient characteristics were balanced through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. Time-to-event outcomes were evaluated using weighted Kaplan-Meier analysis. Overall response rate (ORR) and complete response (CR) rate were compared using weighted odds ratios. The 143 ScHOLAR-5 patients reduced to an effective sample of 85 patients after SMR weighting vs 86 patients in ZUMA-5. Median follow-up time was 25.4 and 23.3 months for SCHOLAR-5 and ZUMA-5. Median overall survival (OS) and progression-free survival (PFS) in SCHOLAR-5 were 59.8 months and 12.7 months and not reached in ZUMA-5. Hazard ratios for OS and PFS were 0.42 (95% confidence interval [CI], 0.21-0.83) and 0.30 (95% CI, 0.18-0.49). The ORR and CR rate were 49.9% and 29.9% in SCHOLAR-5 and 94.2% and 79.1% in ZUMA-5, for odds ratios of 16.2 (95% CI, 5.6-46.9) and 8.9 (95% CI, 4.3-18.3). Compared with available therapies, axi-cel demonstrated an improvement in meaningful clinical endpoints, suggesting axi-cel addresses an important unmet need for r/r FL patients. This trial was registered at www.clinicaltrials.gov as #NCT03105336.

Spotlight on polatuzumab vedotin: new standards for diffuse large B-cell lymphoma?

Despite continuous improvements in the management and treatment of diffuse large B cell lymphoma (DLBCL), approximately 35% of the patients experience relapse or are refractory to frontline chemotherapy. For these patients, outcomes are far from satisfactory, and a real unmet need exists to both improve frontline treatment and create better options for relapsed/refractory disease. Polatuzumab vedotin is an anti-CD79b antibody conjugated to the monomethyl auristatin E (MMAE) microtubule inhibitor. The molecule has recently been under the spotlights for the promising results of the frontline combination with rituximab cyclophosphamide doxorubicin and prednisone (R-CHP) in the phase III POLARIX study, demonstrating improved progression-free survival over standard R-CHOP. A remarkable improvement in terms of complete response rate and overall survival with polatuzumab vedotin has also been achieved by combining polatuzumab with rituximab and bendamustine (pola-BR) over the standard BR for relapsed/refractory patients. Based on the results of these studies, health authorities in several countries granted approval for polatuzumab vedotin both for patients with previously untreated and for relapsed/refractory DLBCL. In this review, we summarize the data of major studies recently concluded with polatuzumab vedotin, and we provide an overview of the ongoing combination trials for frontline and relapsed/refractory DLBCL, outlining reported toxicities.

Diffuse large B-cell lymphoma involving osseous sites: utility of response assessment by PET/CT and good longterm outcomes.

Osseous involvement by diffuse large B-cell lymphoma (DLBCL-bone) is a heterogeneous disease. There is limited data regarding response assessment by positron emission tomography with fluorodeoxyglucose, which may demonstrate residual avidity despite a complete response. We analyzed clinical data of patients with newly diagnosed DLBCL and identified all cases with DLBCL-bone. End of treatment scans were reviewed by two independent experts classifying osseous lesions into Deauville (DV) ≤3; DV ≥4, or reactive uptake in the bone marrow (M), site of fracture (F) or surgery (S). We compared outcomes of DLBCL-bone to other extranodal sites (EN) matched on International Prognotic Index features and regimen. Of 1,860 patients with DLBCL (bone 16%; EN 45%; nodal 39%), 41% had localized disease and 59% advanced. Only 9% (n=27) of patients with initial bone involvement had residual fluorodeoxyglucose avidity at the osseous site. In half of these cases, the uptake was attributed to F/S/M, and of the remaining 13, only two were truly refractory (both with persistent disease at other sites). Overall survival and progression-free survival (PFS) were found to be similar for early- stage nodal DLBCL and DLBCL-bone, but inferior in EN-DLBCL. Advanced-stage disease involving the bone had a similar 5-year PFS to nodal disease and EN-DLBCL. After matching for International Prognotic Index and treatment regiments, PFS between bone and other EN sites was similar. Osseous involvement in DLBCL does not portend a worse prognosis. End of treatment DV ≥4 can be expected in 5-10% of cases, but in the absence of other signs of refractory disease, may be followed expectantly.

Safety and efficacy of tenalisib in combination with romidepsin in patients with relapsed/refractory T-cell lymphoma: results from a phase I/II open-label multicenter study.

Tenalisib, a selective phosphoinositide-3-kinase δ/γ, and salt-inducible-kinase-3 inhibitor has shown efficacy and was well-tolerated in patients with T-cell lymphoma (TCL). In vitro studies suggest a synergistic anti-tumor potential for the combination of tenalisib with the histone-deacetylase inhibitor, romidepsin. This multicenter, open-label, phase I/II study was designed to characterize the safety, efficacy and pharmacokinetics of oral tenalisib twice-daily and intravenous romidepsin administered on days 1, 8 and 15 in 28-day cycles in adults with relapsed/refractory TCL. Phase I/dose escalation determined the maximum tolerated dose (MTD)/optimal doses of tenalisib and romidepsin. The phase II/dose expansion assessed the safety and anti-tumor activity of the combination at MTD/optimal dose. Overall, 33 patients were enrolled. In dose escalation, no dose-limiting toxicity was identified. Hence, the recommended doses for dose expansion were tenalisib 800 mg twice daily orally, and romidepsin 14 mg/m2 intravenous. Overall treatment-emergent adverse events of any grade reported in >15% of patients were nausea, thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, decreased appetite, neutropenia, vomiting, fatigue, anemia, dysgeusia, weight loss, diarrhea, and hypokalemia. Twenty-three patients (69.7%) had related grade ≥3 treatment-emergent adverse events. The overall objective response rate in evaluable patients was 63.0% (peripheral TCL: 75% and cutaneous TCL: 53.3%), with a complete response and partial response of 25.9% and 37.0% respectively. The median duration of response was 5.03 months. Co-administration of tenalisib and romidepsin did not significantly alter the pharmacokinetics of romidepsin. Overall, tenalisib and romidepsin combination demonstrated a favorable safety and efficacy profile supporting its further development for relapsed/refractory TCL (clinicaltrials gov. Identifier: NCT03770000).

Emapalumab as salvage therapy for adults with malignancy-associated hemophagocytic lymphohistiocytosis.

Not available.

Clinical characteristics and outcomes of extranodal stage I diffuse large B-cell lymphoma in the rituximab era.

This retrospective study aimed to better define the characteristics and outcomes of extranodal stage I diffuse large B-cell lymphoma (DLBCL) in the rituximab era. Patients diagnosed with stage I DLBCL from 2001 to 2015 treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) or R-CHOP-like regimens with or without radiation (RT) were included. We identified 1955 patients with newly diagnosed DLBCL, of whom 341 had stage I and were eligible for this analysis. Extranodal presentation was observed in 224 (66%) patients, whereas 117 (34%) had nodal involvement. The most common extranodal sites were as follows: bone, 21%; stomach, 19%; testis, 9%; intestine, 8%; breast, 8%. Overall, 69% extranodal patients and 68% nodal patients received RT. Median follow-up was 5.5 years (interquartile range, 4.3-8.2). Ten-year overall survival (OS) and disease-free survival were 77% (95% confidence interval [CI], 67%-83%) and 77% (95% CI, 68%-85%). In the multivariable analyses, extranodal involvement was associated with worse OS (hazard ratio [HR], 3.44; 95% CI, 1.05-11.30) and progression-free survival (PFS; HR, 3.25; 95% CI, 1.08-9.72) compared with nodal involvement. Consolidation RT was associated with better OS (HR, 0.26; 95% CI, 0.12-0.49) and PFS (HR, 0.35; 95% CI, 0.18-0.69) in the extranodal population; however, the benefit was no longer observed in patients that were positron emission tomography (PET) negative at the end of immunochemotherapy. Relapses occurred usually late (median, 37 months), and the most common sites were the lymph nodes (31%) and the central nervous system (27%). Extranodal stage I DLBCL had a worse outcome than nodal stage 1 DLBCL. End of immunochemotherapy PET results may help select extranodal patients for consolidation RT.

A phase 2 biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas.

Signaling through JAK1 and/or JAK2 is common among tumor and nontumor cells within peripheral T-cell lymphoma (PTCL). No oral therapies are approved for PTCL, and better treatments for relapsed/refractory disease are urgently needed. We conducted a phase 2 study of the JAK1/2 inhibitor ruxolitinib for patients with relapsed/refractory PTCL (n = 45) or mycosis fungoides (MF) (n = 7). Patients enrolled onto 1 of 3 biomarker-defined cohorts: (1) activating JAK and/or STAT mutations, (2) ≥30% pSTAT3 expression among tumor cells by immunohistochemistry, or (3) neither or insufficient tissue to assess. Patients received ruxolitinib 20 mg PO twice daily until progression and were assessed for response after cycles 2 and 5 and every 3 cycles thereafter. The primary endpoint was clinical benefit rate (CBR), defined as the combination of complete response, partial response (PR), and stable disease lasting at least 6 months. Only 1 of 7 patients with MF had CBR (ongoing PR > 18 months). CBR among the PTCL cases (n = 45) in cohorts 1, 2, and 3 were 53%, 45%, and 13% (cohorts 1 & 2 vs 3, P = .02), respectively. Eight patients had CBR > 12 months (5 ongoing), including 4 of 5 patients with T-cell large granular lymphocytic leukemia. In an exploratory analysis using multiplex immunofluorescence, expression of phosphorylated S6, a marker of PI3 kinase or mitogen-activated protein kinase activation, in <25% of tumor cells was associated with response to ruxolitinib (P = .05). Our findings indicate that ruxolitinib is active across various PTCL subtypes and support a precision therapy approach to JAK/STAT inhibition in patients with PTCL. This trial was registered at www.clincialtrials.gov as #NCT02974647.

Treatment patterns and outcomes in relapsed/refractory follicular lymphoma: results from the international SCHOLAR-5 study.

The SCHOLAR-5 study examines treatment patterns and outcomes of real-world follicular lymphoma (FL) patients on 3rd line of treatment (LoT) or higher, for whom existing data are limited. SCHOLAR-5 is a retrospective cohort study using data from adults (≥ 18 years) with grade 1-3a FL, initiating ≥3rd LoT after June 2014 at major lymphoma centers in the US and Europe. Objective response rate (ORR), complete response (CR), progression-free survival (PFS) and overall survival (OS) were analyzed by LoT. Time-to-event outcomes were assessed using Kaplan-Meier methods. Of 128 patients, 87 initiated 3rd LoT, 63 initiated 4th LoT, and 47 initiated 5th LoT. At 1st eligible LoT, 31% progressed within 24-months of 1st LoT anti-CD20 combination therapy, 28% had prior autologous stem cell transplantation, and 31% were refractory to the previous LoT. The most common regimen in each LoT was chemoimmunotherapy; however, experimental drugs were increasingly used at later LoT. In the US, anti-CD20 monotherapy was more common at ≥3rd LoT compared to Europe, where stem cell transplants were more common. ORR at 3rd LoT was 68% (CR 44%), but decreased after each LoT to 37% (CR 22%) in ≥5 LoT. Median OS and PFS at 3rd LoT were 68 and 11 months, respectively, and reduced to 43 and 4 months at ≥5 LoT. Treatments were heterogenous at each LoT in both the US and Europe. Few FL patients achieved CR in later LoT, and duration of response and survival diminished with each subsequent line.

Central nervous system lymphomas-Assessment and treatment and prevention of central nervous system relapse.

In this review focused on lymphoma and the central nervous system (CNS), we summarize recent developments in the management of primary (PCNSL) and secondary CNS lymphoma (SCNSL), treatment of CNS lymphoma in the older population, the neuroradiological assessment of CNS lymphoma and finally highlight the ongoing debate on optimal CNS prophylaxis. The section on PCNSL focuses on the different approaches available for frontline treatment in Europe and the United States and discusses consolidation strategies. We then highlight available strategies to treat PCNSL in the elderly population, an area of unmet need. New therapies aiming at minimizing toxicity and prioritizing quality of life are emerging for these patients. Secondary CNS lymphoma, especially in the relapsed/refractory setting is another area of unmet need, and the efficacy of CAR-T cell therapy is being explored. We provide an overview of the imaging challenges in the neuroradiological assessment of CNS lymphoma. Finally, the section on CNS prophylaxis summarizes recent findings from large retrospective studies challenging the efficacy of present approaches to prophylaxis in higher-risk patients with lymphoma.

Ofatumumab plus HyperCVAD/HD-MA induction leads to high rates of minimal residual disease negativity in patients with newly diagnosed mantle cell lymphoma: Results of a phase 2 study.

BACKGROUND: Ofatumumab is a humanized type 1 anti-CD20 monoclonal antibody. Preclinical studies show improved complement-mediated cytotoxicity (CMC) compared to rituximab in mantle cell lymphoma (MCL). This study evaluates the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O-HyperCVAD) in newly diagnosed MCL. METHODS: In this single-arm phase 2 study, 37 patients were treated with the combination of O-HyperCVAD for 4 or 6 cycles, followed by high dose chemotherapy and autologous stem cell transplant. Primary objectives were overall response rate (ORR) and complete response (CR) rate at the end of therapy. Secondary objectives included minimal residual disease (MRD) negativity, progression-free survival (PFS), and overall survival (OS). RESULTS: Median age was 60 years; ORR was 86% and 73% achieved a CR by modified Cheson criteria. The MRD negativity rate was 78% after 2 cycles of therapy, increasing to 96% at the end of induction; median PFS and OS were 45.5 months and 56 months, respectively. Achieving a post-induction CR by both imaging and flow cytometry was associated with improved PFS and OS. Early MRD negativity (post-2 cycles) was also associated with an improved PFS but not OS. There were 3 deaths while on therapy, and grades 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients. CONCLUSION: The addition of ofatumumab to HyperCVAD/HD-MA led to high rates of MRD negativity by flow cytometry in patients with newly diagnosed MCL. Achieving a CR post-induction by both imaging and flow cytometry is associated with improved overall survival.

Characterization of GECPAR, a noncoding RNA that regulates the transcriptional program of diffuse large B-cell lymphoma.

Enhancers are regulatory regions of DNA, which play a key role in cell-type specific differentiation and development. Most active enhancers are transcribed into enhancer RNA (eRNA) that can regulate transcription of target genes by means of in cis as well as in trans action. eRNA stabilize contacts between distal genomic regions and mediate the interaction of DNA with master transcription factors. Here, we characterized an enhancer eRNA, GECPAR (germinal center proliferative adapter RNA), which is specifically transcribed in normal and neoplastic germinal center B cells from the super-enhancer of POU2AF1, a key regulatory gene of the germinal center reaction. Using diffuse large B-cell lymphoma cell line models, we demonstrated the tumor suppressor activity of GECPAR, which is mediated via its transcriptional regulation of proliferation and differentiation genes, particularly MYC and the Wnt pathway.

An Updated Approach and Understanding of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare subtype of T-cell non-Hodgkin lymphoma that is usually localized to the fluid and capsule surrounding a breast implant. There have only been <1,000 cases and 36 deaths reported to date and the average patient presents 7 to 10 years following initial breast implant placement. Most patients present with delayed seromas, a breast mass, capsular abnormalities, lymphadenopathy, or cutaneous masses. Unlike other forms of non-Hodgkin lymphoma, most cases are cured with surgery alone. The challenge of BIA-ALCL surrounds its rarity-in regard to both its diagnosis as well as the limited available data to guide therapy for more advanced cases. Careful pathology evaluation to analyze both the fluid surrounding the capsule and the capsule itself is critical. Studies to identify which patients are at greater risk of development of this rare entity are ongoing.

T-Cell Lymphomas, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase-negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.

KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study.

In recent years, the outcome of mantle cell lymphoma (MCL) has improved, especially in younger patients, receiving cytarabine-containing chemoimmunotherapy and autologous stem cell transplantation. Nevertheless, a proportion of MCL patients still experience early failure. To identify biomarkers anticipating failure of intensive chemotherapy in MCL, we performed target resequencing and DNA profiling of purified tumor samples collected from patients enrolled in the prospective FIL-MCL0208 phase 3 trial (high-dose chemoimmunotherapy followed by autologous transplantation and randomized lenalidomide maintenance). Mutations of KMT2D and disruption of TP53 by deletion or mutation associated with an increased risk of progression and death, both in univariate and multivariate analysis. By adding KMT2D mutations and TP53 disruption to the MIPI-c backbone, we derived a new prognostic index, the "MIPI-genetic" ("MIPI- g"). The "MIPI-g" improved the model discrimination ability compared to the MIPI-c alone, defining three risk groups: i) low-risk patients (4-year progression free survival and overall survival of 72.0% and 94.5%); ii) inter-mediate-risk patients (4-year progression free survival and overall survival of 42.2% and 65.8%) and iii) high-risk patients (4-year progression free survival and overall survival of 11.5% and 44.9%). Our results: i) confirm that TP53 disruption identifies a high-risk population characterized by poor sensitivity to conventional or intensified chemotherapy; ii) provide the pivotal evidence that patients harboring KMT2D mutations share the same poor outcome as patients harboring TP53 disruption; and iii) allow to develop a tool for the identification of high-risk MCL patients for whom novel therapeutic strategies need to be investigated. (Trial registered at clinicaltrials.gov identifier: NCT02354313).

Predictors of cardiovascular outcome and rehospitalization in elderly patients with heart failure.

BACKGROUND: Heart failure (HF) is a major public health problem and represents the only cardiac disease continuing to increase in prevalence, in particular among elderly patients. The frequent rehospitalizations have a negative impact on quality of life of patients with HF, constituting a substantial cost for patients and the health system. The aim of this review was to look into biochemical, echocardiographic and socioeconomical parameters as predictors of clinical outcomes and rehospitalizations. METHODS: This narrative review is based on the material searched for and obtained via PubMed from January 2000 up to March 2018. The search terms we used were as follows: "elderly, heart failure, cardiovascular" in combination with "biomarker, echocardiography and hospitalization." RESULTS: This review analyses the potential predictive role of biochemical and echocardiographic and socioeconomical parameters on clinical outcomes (particularly cardiovascular) and hospital readmissions in patients with chronic HF. We focused on risk stratification of elderly patients with HF, who constitute a category of frail subjects at higher risk for readmission to hospital. CONCLUSIONS: In elderly subjects with chronic HF, the risk stratification could benefit of a multiparametric approach combining biochemical, echocardiographic, demographic and socioeconomical parameters, thus ensuring a better quality of life and at the same time a better allocation of financial resources.

A Comparison of the Conditioning Regimens BEAM and FEAM for Autologous Hematopoietic Stem Cell Transplantation in Lymphoma: An Observational Study on 1038 Patients From Fondazione Italiana Linfomi.

BEAM (carmustine [bis-chloroethylnitrosourea (BCNU)]-etoposide-cytarabine-melphalan) chemotherapy is the standard conditioning regimen for autologous stem cell transplantation (ASCT) in lymphomas. Owing to BCNU shortages, many centers switched to fotemustine-substituted BEAM (FEAM), lacking proof of equivalence. We conducted a retrospective cohort study in 18 Italian centers to compare the safety and efficacy of BEAM and FEAM regimens for ASCT in lymphomas performed from 2008 to 2015. We enrolled 1038 patients (BEAM = 607, FEAM = 431), of which 27% had Hodgkin lymphoma (HL), 14% indolent non-Hodgkin lymphoma (NHL), and 59% aggressive NHL. Baseline characteristics including age, sex, stage, B-symptoms, extranodal involvement, previous treatments, response before ASCT, and overall conditioning intensity were well balanced between BEAM and FEAM; notable exceptions were median ASCT year (BEAM = 2011 versus FEAM = 2013, P < .001), Sorror score ≥3 (BEAM = 15% versus FEAM = 10%, P = .017), and radiotherapy use (BEAM = 18% versus FEAM = 10%, P < .001). FEAM conditioning resulted in higher rates of gastrointestinal and infectious toxicities, including severe oral mucositis grade ≥3 (BEAM = 31% versus FEAM = 44%, P < .001), and sepsis from Gram-negative bacteria (mean isolates/patient: BEAM = .1 versus FEAM = .19, P < .001). Response status at day 100 post-ASCT (overall response: BEAM = 91% versus FEAM = 88%, P = .42), 2-year overall survival (83.9%; 95% confidence interval [CI], 81.5% to 86.1%) and progression-free survival (70.3%; 95% CI, 67.4% to 73.1%) were not different in the two groups. Mortality from infection was higher in the FEAM group (subhazard ratio, 1.99; 95% CI, 1.02 to 3.88; P = .04). BEAM and FEAM do not appear different in terms of survival and disease control. However, due to concerns of higher toxicity, fotemustine substitution in BEAM does not seem justified, if not for easier supply.

Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas.

Aggressive double- and triple-hit (DH/TH) diffuse large B-cell lymphomas (DLBCLs) feature activation of Hsp90 stress pathways. Herein, we show that Hsp90 controls posttranscriptional dynamics of key messenger RNA (mRNA) species including those encoding BCL6, MYC, and BCL2. Using a proteomics approach, we found that Hsp90 binds to and maintains activity of eIF4E. eIF4E drives nuclear export and translation of BCL6, MYC, and BCL2 mRNA. eIF4E RNA-immunoprecipitation sequencing in DLBCL suggests that nuclear eIF4E controls an extended program that includes B-cell receptor signaling, cellular metabolism, and epigenetic regulation. Accordingly, eIF4E was required for survival of DLBCL including the most aggressive subtypes, DH/TH lymphomas. Indeed, eIF4E inhibition induces tumor regression in cell line and patient-derived tumorgrafts of TH-DLBCL, even in the presence of elevated Hsp90 activity. Targeting Hsp90 is typically limited by counterregulatory elevation of Hsp70B, which induces resistance to Hsp90 inhibitors. Surprisingly, we identify Hsp70 mRNA as an eIF4E target. In this way, eIF4E inhibition can overcome drug resistance to Hsp90 inhibitors. Accordingly, rational combinatorial inhibition of eIF4E and Hsp90 inhibitors resulted in cooperative antilymphoma activity in DH/TH DLBCL in vitro and in vivo.