Immunologic predictors of vaccine responsiveness in patients with lymphoma and CLL.

Patients with B-cell lymphomas have altered cellular components of vaccine responses due to malignancy and therapy, and the optimal timing of vaccination relative to therapy remains unknown. SARS-CoV-2 vaccines created an opportunity for new insights in vaccine timing because patients were challenged with a novel antigen across multiple phases of treatment. We studied serologic mRNA vaccine response in retrospective and prospective cohorts with lymphoma and CLL, paired with clinical and research immune parameters. Reduced serologic response was observed more frequently during active therapies, but non-response was also common within observation and post-treatment groups. Total IgA and IgM correlated with successful vaccine response. In individuals treated with CART-19, non-response was associated with reduced B and T follicular helper cells. Predictors of vaccine response varied by disease and therapeutic group, and therefore further studies of immune health during and after cancer therapies are needed to allow individualized vaccine timing.

2024 Update: Advances in the risk stratification and management of large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with varying clinical outcomes. Our understanding of its molecular makeup continues to improve risk stratification, and artificial-intelligence and ctDNA-based analyses have the potential to enhance risk assessment and disease monitoring. R-CHOP and Pola-R-CHP are used in the frontline setting; chimeric antigen receptor therapy (CART) is now the new standard-of-care for most with primary refractory disease; both CART and autologous stem cell transplantation are utilized in the relapsed and refractory setting. In this review, we summarize the classification and management of DLBCL with an emphasis on recent advances in the field.

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.

Fimepinostat (CUDC-907) in patients with relapsed/refractory diffuse large B cell and high-grade B-cell lymphoma: report of a phase 2 trial and exploratory biomarker analyses.

Fimepinostat (CUDC-907), a first-in-class oral small-molecule inhibitor of histone deacetylase and phosphatidylinositol 3-kinase, demonstrated efficacy in a phase 1 study of patients with relapsed/refractory (R/R) diffuse large and high-grade B-cell lymphomas (DLBCL/HGBL), particularly those with increased MYC protein expression and/or MYC gene rearrangement/copy number gain (MYC-altered disease). Therefore, a phase 2 study of fimepinostat was conducted in this patient population with 66 eligible patients treated. The primary end-point of overall response (OR) rate for patients with MYC-IHC ≥40% (n = 46) was 15%. Subsequently, exploratory pooled analyses were performed including patients treated on both the phase 1 and 2 studies based upon the presence of MYC-altered disease as well as a biomarker identified by Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER). For these patients with MYC-altered disease (n = 63), the overall response (OR) rate was 22% with seven responding patients remaining on treatment for approximately two years or longer, and VIPER yielded a three-protein biomarker classification with positive and negative predictive values of ≥85%. Prolonged durations of response were achieved by patients with MYC-altered R/R DLBCL/HGBL treated with single-agent fimepinostat. Combination therapies and/or biomarker-based patient selection strategies may lead to higher response rates in future clinical trials.

Brentuximab vedotin in the treatment of CD30+ PTCL.

The development of brentuximab vedotin has opened a new era in the management of peripheral T-cell lymphomas (PTCLs). The improved outcomes with brentuximab vedotin (BV) in combination with cyclophosphamide, doxorubicin, and prednisone (BV-CHP) vs cyclophosphamide, doxorubicin, vincristine, and prednisone in the ECHELON-2 trial are practice changing for common nodal CD30+ PTCLs. Questions regarding the optimal cutoff of CD30 expression for BV-CHP therapy and the efficacy and safety of BV-CHP in less common subtypes of CD30+ PTCL subtypes await clarification.

A novel model of controlling PD-L1 expression in ALK+ anaplastic large cell lymphoma revealed by CRISPR screening.

The success of programmed cell death protein 1 (PD-1)/PD-L1-based immunotherapy highlights the critical role played by PD-L1 in cancer progression and reveals an urgent need to develop new approaches to attenuate PD-L1 function by gaining insight into how its expression is controlled. Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 as a result of the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent on the nucleophosmin-ALK oncoprotein activation of STAT3, as well as a signalosome containing GRB2/SOS1, which activates the MEK-ERK and PI3K-AKT signaling pathways. These signaling networks, through STAT3 and the GRB2/SOS1, ultimately induce PD-L1 expression through the action of transcription factors IRF4 and BATF3 on the enhancer region of the PD-L1 gene. IRF4 and BATF3 are essential for PD-L1 upregulation, and IRF4 expression is correlated with PD-L1 levels in primary ALK+ ALCL tissues. Targeting this oncogenic signaling pathway in ALK+ ALCL largely inhibited the ability of PD-L1-mediated tumor immune escape when cocultured with PD-1-positive T cells and natural killer cells. Thus, our identification of this previously unrecognized regulatory hub not only accelerates our understanding of the molecular circuitry that drives tumor immune escape but also provides novel opportunities to improve immunotherapeutic intervention strategies.

Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas.

We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).

Intensive induction regimens after deferring initial therapy for mantle cell lymphoma are not associated with improved survival.

INTRODUCTION: While most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent-behaving disease can safely defer treatment. In this subgroup, we evaluated the importance of treatment intensity in patients with MCL who defer initial therapy. METHODS: Out of 1134 patients with MCL from 12 academic centers, we analyzed 219 patients who initiated therapy at least 90 days after diagnosis. Patients who received induction with high-dose cytarabine and/or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy (n = 88) while all other approaches were non-intensive (n = 131). RESULTS: There was no difference in progression-free (PFS; P = .224) or overall survival (OS; P = .167) in deferred patients who received non-intensive vs. intensive therapy. Additionally, univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Treatment at an academic center (HR 0.43, P = .015) was associated with improved OS in both univariate and multivariate models, while intensity of treatment was not associated with improved OS in either model. CONCLUSIONS: These results indicate that intensified initial treatment is not associated with improved survival after deferring initial therapy, although prospective studies are needed to determine which of these patients with MCL may benefit from intensive therapy.

2021 Update on Diffuse large B cell lymphoma: A review of current data and potential applications on risk stratification and management.

Diffuse large B cell lymphoma (DLBCL), the most common type of Non-Hodgkin lymphoma (NHL), comprises a heterogeneous group of diseases with different biology, clinical presentations, and response to treatment. R-CHOP remains the mainstay of therapy and can achieve long-term disease control in nearly 90% of patients presenting with limited-stage and in up to 60% of those presenting with advanced stages. Advances on the understanding of the genetic landscape and molecular features of DLBCL have identified high-risk subsets with poor outcomes to chemo-immunotherapy that are actively being studied in clinical trials. Novel therapies could potentially improve outcomes for patients with high-risk disease. Studies evaluating risk-adapted therapy based on classification by cell of origin (COO) and molecular features are ongoing. Developments in the fields of immunotherapy, mostly with adoptive T-cell therapy, have significantly improved the outcomes of patients with relapsed refractory disease. In this review, we will summarize the recent data and discuss ongoing efforts to improve DLBCL treatment in the frontline and relapsed refractory settings.

Multi-center analysis of practice patterns and outcomes of younger and older patients with mantle cell lymphoma in the rituximab era.

Clinical outcomes and predictors of survival in patients with newly diagnosed mantle cell lymphoma (MCL) treated in the rituximab era (2000-2015) at 12 US academic centers were assessed to identify determinants of survival across age groups. Objectives were to characterize and compare practice patterns, outcomes and prognostic factors for survival in younger patients (age < 65) and older patients (age ≥ 65 years). Among 1162 patients included, 697 were younger and 465 were older. In younger patients, 2-year progression free survival (PFS) and overall survival (OS) rates were 79% and 92% respectively; blastoid histology, ECOG ≥ 2, and lack of maintenance rituximab (MR) remained statistically relevant to poor OS on univariate analysis (UVA) and multivariate analysis (MVA). In older patients, 2-year PFS and OS rates were 67% and 86% respectively; lack of maintenance rituximab remained significantly associated with inferior PFS and OS on UVA and MVA (p < 0.001). Two-year PFS rates were 79%, and 67% and 2-year OS rates were 92% and 86% for ages < 65 and ≥ 65 respectively (p < 0.001). First-line high-dose cytarabine exposure and/or MR lessened the negative impact of age on survival. Taken collectively, survival outcomes for older patients remain inferior to those of younger patients in the rituximab era. However, maintenance rituximab and potentially high-dose cytarabine-based induction can mitigate the negative impact of age on survival.

Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure.

BACKGROUND: Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown. METHODS: Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy. RESULTS: In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy. CONCLUSIONS: Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients.

Checkpoint blockade treatment sensitises relapsed/refractory non-Hodgkin lymphoma to subsequent therapy.

Patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) have limited options for salvage, and checkpoint blockade therapy (CBT) has little efficacy. Usage in solid malignancies suggests that CBT sensitises tumours to subsequent chemotherapy. We performed the first analysis of CBT on subsequent NHL treatment. Seventeen North American centres retrospectively queried records. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment. Secondary aims included progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Fifty-nine patients (68% aggressive NHL, 69% advanced disease) were included. Patients received a median of three therapies before CBT. Fifty-three (90%) discontinued CBT due to progression. Post-CBT regimens included chemotherapy (49%), targeted therapy (30%), clinical trial (17%), transplant conditioning (2%) and chimeric antigen receptor T cell (CAR-T) therapy (2%). The ORR to post-CBT treatment was 51%, with median PFS of 6·1 months. In patients with at least stable disease (SD) to post-CBT, the median DOR was significantly longer than to pre-CBT (310 vs. 79 days, P = 0·005) suggesting sensitisation. Nineteen patients were transplanted after post-CBT therapy. Median overall survival was not reached, nor affected by regimen. Prospective trials are warranted, as this may offer R/R NHL patients a novel therapeutic approach.

Impact of Treatment Beyond Progression with Immune Checkpoint Blockade in Hodgkin Lymphoma.

Atypical response patterns following immune checkpoint blockade (ICB) in Hodgkin lymphoma (HL) led to the concept of continuation of treatment beyond progression (TBP); however, the longitudinal benefit of this approach is unclear. We therefore performed a retrospective analysis of 64 patients treated with ICB; 20 who received TBP (TBP cohort) and 44 who stopped ICB at initial progression (non-TBP cohort). The TBP cohort received ICB for a median of 4.7 months after initial progression and delayed subsequent treatment by a median of 6.6 months. Despite receiving more prior lines of therapy, the TBP cohort achieved longer progression-free survival with post-ICB treatment (median, 17.5 months vs. 6.1 months, p = .035) and longer time-to-subsequent treatment failure, defined as time from initial ICB progression to failure of subsequent treatment (median, 34.6 months vs. 9.9 months, p = .003). With the limitations of a retrospective study, these results support the clinical benefit of TBP with ICB for selected patients.

NCCN Guidelines Insights: T-Cell Lymphomas, Version 1.2021.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

NCCN Guidelines Insights: Primary Cutaneous Lymphomas, Version 2.2020.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), and Sézary syndrome (SS) is a rare erythrodermic and leukemic subtype of CTCL characterized by significant blood involvement. Although early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary for the treatment of advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as romidepsin, brentuximab vedotin, and mogamulizumab. These NCCN Guidelines Insights discuss the diagnosis and management of MF and SS (with a focus on systemic therapy).

Follicular Lymphoma: Recent and Emerging Therapies, Treatment Strategies, and Remaining Unmet Needs.

Follicular lymphoma (FL) is a heterogeneous disease with varying prognosis owing to differences in clinical, laboratory, and disease parameters. Although generally considered incurable, prognosis for early- and advanced-stage disease has improved because of therapeutic advances, several of which have resulted from elucidation of the biologic and molecular basis of the disease. The choice of treatment for FL is highly dependent on patient and disease characteristics. Several tools are available for risk stratification, although limitations in their routine clinical use exist. For limited disease, treatment options include radiotherapy, rituximab monotherapy or combination regimens, and surveillance. Treatment of advanced disease is often determined by tumor burden, with surveillance or rituximab considered for low tumor burden and chemoimmunotherapy for high tumor burden disease. Treatment for relapsed or refractory disease is influenced by initial first-line therapy and the duration and quality of the response. Presently, there is no consensus for treatment of patients with early or multiply relapsed disease; however, numerous agents, combination regimens, and transplant options have demonstrated efficacy. Although the number of therapies available to treat FL has increased together with an improved understanding of the underlying biologic basis of disease, the best approach to select the most appropriate treatment strategy for an individual patient at a particular time continues to be elucidated. This review considers prognostication and the evolving treatment landscape of FL, including recent and emergent therapies as well as remaining unmet needs. IMPLICATIONS FOR PRACTICE: In follicular lymphoma, a personalized approach to management based on disease biology, patient characteristics, and other factors continues to emerge. However, application of current management requires an understanding of the available therapeutic options for first-line treatment and knowledge of current development in therapies for previously untreated and for relapsed or refractory disease. Thus, this work reviews for clinicians the contemporary data in follicular lymphoma, from advances in characterizing disease biology to current treatments and emerging novel therapies.

AIDS-Related Kaposi Sarcoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

As treatment of HIV has improved, people living with HIV (PLWH) have experienced a decreased risk of AIDS and AIDS-defining cancers (non-Hodgkin's lymphoma, Kaposi sarcoma, and cervical cancer), but the risk of Kaposi sarcoma in PLWH is still elevated about 500-fold compared with the general population in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AIDS-Related Kaposi Sarcoma provide diagnosis, treatment, and surveillance recommendations for PLWH who develop limited cutaneous Kaposi sarcoma and for those with advanced cutaneous, oral, visceral, or nodal disease.

NCCN Guidelines Insights: T-Cell Lymphomas, Version 2.2018.

Natural killer (NK)/T-cell lymphomas are a rare and distinct subtype of non-Hodgkin's lymphomas. NK/T-cell lymphomas are predominantly extranodal and most of these are nasal type, often localized to the upper aerodigestive tract. Because extranodal NK/T-cell lymphomas (ENKL) are rare malignancies, randomized trials comparing different regimens have not been conducted to date and standard therapy has not yet been established for these patients. These NCCN Guidelines Insights discuss the recommendations for the diagnosis and management of patients with ENKL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Cancer in People Living With HIV, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.

People living with HIV (PLWH) are diagnosed with cancer at an increased rate over the general population and generally have a higher mortality due to delayed diagnoses, advanced cancer stage, comorbidities, immunosuppression, and cancer treatment disparities. Lack of guidelines and provider education has led to substandard cancer care being offered to PLWH. To fill that gap, the NCCN Guidelines for Cancer in PLWH were developed; they provide treatment recommendations for PLWH who develop non-small cell lung cancer, anal cancer, Hodgkin lymphoma, and cervical cancer. In addition, the NCCN Guidelines outline advice regarding HIV management during cancer therapy; drug-drug interactions between antiretroviral treatments and cancer therapies; and workup, radiation therapy, surgical management, and supportive care in PLWH who have cancer.