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13 pages, 1156 KiB

Open AccessArticle

Improved Survival of Lymphoma Patients with COVID-19 in the Modern Treatment and Vaccination Era

by Alexandra Della Pia, Charles Zhao, Parul Jandir, Amolika Gupta, Mark Batistick, Gee Youn (Geeny) Kim, Yi Xia, Jaeil Ahn, Gabriella Magarelli, Brittany Lukasik, Lori A. Leslie, Andre H. Goy, Andrew Ip and Tatyana A. Feldman

Cancers 2022, 14(17), 4252; https://doi.org/10.3390/cancers14174252 - 31 Aug 2022

Cited by 5 | Viewed by 2908

Abstract

Lymphoma patients are at greater risk of severe consequences from COVID-19 infection, yet most reports of COVID-19-associated outcomes were published before the advent of COVID-19 vaccinations and monoclonal antibodies (mAbs). In this retrospective study, we report the real-world outcomes of 68 lymphoma or [...] Read more.

Lymphoma patients are at greater risk of severe consequences from COVID-19 infection, yet most reports of COVID-19-associated outcomes were published before the advent of COVID-19 vaccinations and monoclonal antibodies (mAbs). In this retrospective study, we report the real-world outcomes of 68 lymphoma or CLL patients who developed COVID-19 infection during the omicron surge in the US. We found that 34% of patients were hospitalized as a result of COVID-19 infection. The death rate due to COVID-19 was 9% (6/68) in the overall population and 26% (6/23) in hospitalized patients. During the preintervention COVID-19 era, the mortality rate reported in cancer patients was 34%, which increased to 60.2% in hospitalized patients. Thus, the death rates in our study were much lower when compared to those in cancer patients earlier in the pandemic, and may be attributed to modern interventions. In our study, 60% (18/30) of patients with serology data available did not develop anti-COVID-19 spike protein antibodies following vaccination. Most patients (74%, 17/23) who were hospitalized due to COVID-19 infection did not receive COVID-19 mAb treatment. Our results pointed to the importance of humoral immunity and the protective effect of COVID-19 mAbs in improving outcomes in lymphoma patients. Full article

(This article belongs to the Special Issue Non-Hodgkin Lymphomas)

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20 pages, 1408 KiB

Open AccessArticle

Circulating microRNAs in Cerebrospinal Fluid and Plasma: Sensitive Tool for Detection of Secondary CNS Involvement, Monitoring of Therapy and Prediction of CNS Relapse in Aggressive B-NHL Lymphomas

by Pavle Krsmanovic, Heidi Mocikova, Kamila Chramostova, Magdalena Klanova, Marie Trnkova, Michal Pesta, Peter Laslo, Robert Pytlik, Tomas Stopka, Marek Trneny and Vit Pospisil

Cancers 2022, 14(9), 2305; https://doi.org/10.3390/cancers14092305 - 6 May 2022

Cited by 6 | Viewed by 2284

Abstract

Lymphoma with secondary central nervous system (CNS) involvement represents one of the most aggressive malignancies, with poor prognosis and high mortality. New diagnostic tools for its early detection, response evaluation, and CNS relapse prediction are needed. We analyzed circulating microRNAs in the cerebrospinal [...] Read more.

Lymphoma with secondary central nervous system (CNS) involvement represents one of the most aggressive malignancies, with poor prognosis and high mortality. New diagnostic tools for its early detection, response evaluation, and CNS relapse prediction are needed. We analyzed circulating microRNAs in the cerebrospinal fluid (CSF) and plasma of 162 patients with aggressive B-cell non-Hodgkin’s lymphomas (B-NHL) and compared their levels in CNS-involving lymphomas versus in systemic lymphomas, at diagnosis and during treatment and CNS relapse. We identified a set of five oncogenic microRNAs (miR-19a, miR-20a, miR-21, miR-92a, and miR-155) in CSF that detect, with high sensitivity, secondary CNS lymphoma involvement in aggressive B-NHL, including DLBCL, MCL, and Burkitt lymphoma. Their combination into an oncomiR index enables the separation of CNS lymphomas from systemic lymphomas or nonmalignant controls with high sensitivity and specificity, and high Receiver Operating Characteristics (DLBCL AUC = 0.96, MCL = 0.93, BL = 1.0). Longitudinal analysis showed that oncomiR levels reflect treatment efficacy and clinical outcomes, allowing their monitoring and prediction. In contrast to conventional methods, CSF oncomiRs enable detection of early and residual CNS involvement, as well as parenchymal involvement. These circulating oncomiRs increase 1–4 months before CNS relapse, allowing its early detection and improving the prediction of CNS relapse risk in DLBCL. Similar effects were detectable, to a lesser extent, in plasma. Full article

(This article belongs to the Special Issue Non-Hodgkin Lymphomas)

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16 pages, 2324 KiB

Open AccessArticle

A Prognostic Model Using Post-Steroid Neutrophil-Lymphocyte Ratio Predicts Overall Survival in Primary Central Nervous System Lymphoma

by Yu Tung Lo, Vivian Yujing Lim, Melissa Ng, Ya Hwee Tan, Jianbang Chiang, Esther Wei Yin Chang, Jason Yongsheng Chan, Eileen Yi Ling Poon, Nagavalli Somasundaram, Mohamad Farid Bin Harunal Rashid, Miriam Tao, Soon Thye Lim and Valerie Shiwen Yang

Cancers 2022, 14(7), 1818; https://doi.org/10.3390/cancers14071818 - 3 Apr 2022

Cited by 7 | Viewed by 4056

Abstract

Background: Ratios of differential blood counts (hematological indices, HIs) had been identified as prognostic variables in various cancers. In primary central nervous system lymphomas (PCNSLs), higher baseline neutrophil-lymphocyte ratio (NLR) in particular was found to portend a worse overall survival. However, it was [...] Read more.

Background: Ratios of differential blood counts (hematological indices, HIs) had been identified as prognostic variables in various cancers. In primary central nervous system lymphomas (PCNSLs), higher baseline neutrophil-lymphocyte ratio (NLR) in particular was found to portend a worse overall survival. However, it was often observed that differential counts shift drastically following steroid administration. Moreover, steroids are an important part of the arsenal against PCNSL due to its potent lymphotoxic effects. We showed that the effect of steroids on differential blood cell counts and HIs could be an early biomarker for subsequent progression-free (PFS) and overall survival (OS). Methods: This study retrospectively identified all adult patients who received a brain biopsy from 2008 to 2019 and had histologically confirmed PCNSL, and included only those who received chemoimmunotherapy, with documented use of corticosteroids prior to treatment induction. Different blood cell counts and HIs were calculated at three time-points: baseline (pre steroid), pre chemoimmunotherapy (post steroid) and post chemoimmunotherapy. Tumor progression and survival data were collected and analyzed through Kaplan–Meier estimates and Cox regression. We then utilized selected variables found to be significant on Kaplan–Meier analysis to generate a decision-tree prognostic model, the NNI-NCCS score. Results: A total of 75 patients who received chemoimmunotherapy were included in the final analysis. For NLR, OS was longer with higher pre-chemoimmunotherapy (post-steroid) NLR (dichotomized at NLR ≥ 4.0, HR 0.42, 95% CI: 0.21–0.83, p = 0.01) only. For platelet-lymphocyte ratio (PLR) and lymphocyte-monocyte ratio (LMR), OS was better for lower post-chemoimmunotherapy PLR (dichotomized at PLR ≥ 241, HR 2.27, 95% CI: 1.00 to 5.18, p = 0.05) and lower pre-chemoimmunotherapy (post-steroid) LMR (dichotomized at LMR ≥25.7, HR 2.17, 95% CI: 1.10 to 4.31, p = 0.03), respectively, only. The decision-tree model using age ≤70, post-steroid NLR >4.0, and pre-steroid (baseline) NLR <2.5 and the division of patients into three risk profiles—low, medium, and high—achieved good accuracy (area-under-curve of 0.78), with good calibration (Brier score: 0.16) for predicting 2-year overall survival. Conclusion: We found that post-steroid NLR, when considered together with baseline NLR, has prognostic value, and incorporation into a prognostic model allowed for accurate and well-calibrated stratification into three risk groups. Full article

(This article belongs to the Special Issue Non-Hodgkin Lymphomas)

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11 pages, 849 KiB

Open AccessArticle

Treatment with Idelalisib in Patients with Relapsed or Refractory Follicular Lymphoma: The Observational Italian Multicenter FolIdela Study

by Beatrice Casadei, Lisa Argnani, Alessandro Broccoli, Caterina Patti, Piero Maria Stefani, Antonio Cuneo, Gloria Margiotta Casaluci, Carlo Visco, Guido Gini, Fabrizio Pane, Francesco D’Alò, Debora Luzi, Maria Cantonetti, Samantha Pozzi, Gerardo Musuraca, Chiara Rosignoli, Annalisa Arcari, Sofya Kovalchuk, Monica Tani, Maria Chiara Tisi, Mario Petrini, Vittorio Stefoni and Pier Luigi Zinzani Show full author list Hide full author list

Cancers 2022, 14(3), 654; https://doi.org/10.3390/cancers14030654 - 27 Jan 2022

Cited by 3 | Viewed by 2066

Abstract

Follicular lymphoma (FL) is an indolent hematological disease, often responsive to the first line of treatment, but characterized by repeated relapses. The therapeutic algorithm for relapsed/refractory FL patients comprises phosphatidylinositol 3-kinase inhibitors. Idelalisib showed anticancer activity, while inducing a significant rate of toxicities. [...] Read more.

Follicular lymphoma (FL) is an indolent hematological disease, often responsive to the first line of treatment, but characterized by repeated relapses. The therapeutic algorithm for relapsed/refractory FL patients comprises phosphatidylinositol 3-kinase inhibitors. Idelalisib showed anticancer activity, while inducing a significant rate of toxicities. Since the evidence in the literature on its use in normal clinical practice is scarce, a retrospective multicenter study was conducted to evaluate effectiveness and tolerability in a real-life context. Seventy-two patients with a median age at diagnosis of 57.2 years—mostly with an advanced stage (88.9%) and relapsed to the most recent therapy (79.1%)—were enrolled. The median number of prior therapies was three (20.8% refractory to the last therapy before idelalisib). With a median number of 4 months of treatment, the overall response rate was 41.7% (20.8% complete responses). Median disease-free survival and overall survival were achieved at 8.4 months and at 4 years, respectively. Forty-four percent of patients experienced at least one drug-related toxicity: 6.9% hematological ones and 43% non-hematological. The study confirmed that idelalisib has anticancer effectiveness and an acceptable safety profile in relapsed/refractory FL with unfavorable prognostic characteristics, even in the context of normal clinical practice. Full article

(This article belongs to the Special Issue Non-Hodgkin Lymphomas)

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12 pages, 1724 KiB

Open AccessArticle

Soluble PD-1 but Not PD-L1 Levels Predict Poor Outcome in Patients with High-Risk Diffuse Large B-Cell Lymphoma

by Heli Vajavaara, Julie Bondgaard Mortensen, Suvi-Katri Leivonen, Ida Monrad Hansen, Maja Ludvigsen, Harald Holte, Judit Jørgensen, Mette Bjerre, Francesco d’Amore and Sirpa Leppä

Cancers 2021, 13(3), 398; https://doi.org/10.3390/cancers13030398 - 22 Jan 2021

Cited by 16 | Viewed by 3915

Abstract

Interaction of checkpoint receptor programmed death 1 (PD-1) with its ligand 1 (PD-L1) downregulates T cell effector functions and thereby leads to tumor immune escape. Here, we aimed to determine the clinical significance of soluble PD-1 (sPD-1) and soluble PD-L1 (sPD-L1) in patients [...] Read more.

Interaction of checkpoint receptor programmed death 1 (PD-1) with its ligand 1 (PD-L1) downregulates T cell effector functions and thereby leads to tumor immune escape. Here, we aimed to determine the clinical significance of soluble PD-1 (sPD-1) and soluble PD-L1 (sPD-L1) in patients with diffuse large B-cell lymphoma (DLBCL). We included 121 high-risk DLBCL patients treated in the Nordic NLG-LBC-05 trial with dose-dense immunochemotherapy. sPD-1 and sPD-L1 levels were measured from serum samples collected prior to treatment, after three immunochemotherapy courses, and at the end of therapy. sPD-1 and sPD-L1 levels were the highest in pretreatment samples, declining after three courses, and remaining low post-treatment. Pretreatment sPD-1 levels correlated with the quantities of PD1+ T cells in tumor tissue and translated to inferior survival, while no correlation was observed between sPD-L1 levels and outcome. The relative risk of death was 2.9-fold (95% CI 1.12–7.75, p = 0.028) and the risk of progression was 2.8-fold (95% CI 1.16–6.56, p = 0.021) in patients with high pretreatment sPD-1 levels compared to those with low levels. In conclusion, pretreatment sPD-1 level is a predictor of poor outcome after dose-dense immunochemotherapy and may be helpful in further improving molecular risk profiles in DLBCL. Full article

(This article belongs to the Special Issue Non-Hodgkin Lymphomas)

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Review

Jump to: Research

21 pages, 367 KiB

Open AccessReview

Tumor Microenvironment and Immunotherapy-Based Approaches in Mantle Cell Lymphoma

by Khalil Saleh, Morgane Cheminant, David Chiron, Barbara Burroni, Vincent Ribrag and Clémentine Sarkozy

Cancers 2022, 14(13), 3229; https://doi.org/10.3390/cancers14133229 - 30 Jun 2022

Cited by 13 | Viewed by 3441

Abstract

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t(11;14) (q13;q32) and a poor response to rituximab–anthracycline-based chemotherapy. High-dose cytarabine-based regimens offer a durable response, but an important number of MCL patients are not eligible for intensive [...] Read more.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t(11;14) (q13;q32) and a poor response to rituximab–anthracycline-based chemotherapy. High-dose cytarabine-based regimens offer a durable response, but an important number of MCL patients are not eligible for intensive treatment and are ideal candidates for novel targeted therapies (such as BTK, proteasome or BCL2 inhibitors, Immunomodulatory Drugs (IMiDs), bispecific antibodies, or CAR-T cell therapy). On the bench side, several studies aiming to integrate the tumor within its ecosystem highlighted a critical role of the tumor microenvironment (TME) in the expansion and resistance of MCL. This led to important insights into the role of the TME in the management of MCL, including potential targets and biomarkers. Indeed, targeted agents often have a combined mechanism of action on the tumor B cell but also on the tumor microenvironment. The aim of this review is to briefly describe the current knowledge on the biology of the TME in MCL and expose the results of the different therapeutic strategies integrating the TME in this disease. Full article

(This article belongs to the Special Issue Non-Hodgkin Lymphomas)

25 pages, 443 KiB

Open AccessReview

Targeted Agents in the Treatment of Indolent B-Cell Non-Hodgkin Lymphomas

by Adrian Minson, Constantine Tam, Michael Dickinson and John F. Seymour

Cancers 2022, 14(5), 1276; https://doi.org/10.3390/cancers14051276 - 1 Mar 2022

Cited by 3 | Viewed by 3406

Abstract

Targeted therapies continue to change the landscape of lymphoma treatment, resulting in improved therapy options and patient outcomes. Numerous agents are now approved for use in the indolent lymphomas and many others under development demonstrate significant promise. In this article, we review the [...] Read more.

Targeted therapies continue to change the landscape of lymphoma treatment, resulting in improved therapy options and patient outcomes. Numerous agents are now approved for use in the indolent lymphomas and many others under development demonstrate significant promise. In this article, we review the landscape of targeted agents that apply to the indolent lymphomas, predominantly follicular lymphoma, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinaemia and marginal zone lymphoma. The review covers small molecule inhibitors, immunomodulators and targeted immunotherapies, as well as presenting emerging and promising combination therapies. Full article

(This article belongs to the Special Issue Non-Hodgkin Lymphomas)

30 pages, 908 KiB

Open AccessEditor’s ChoiceReview

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

by Tadeusz Robak, Magda Witkowska and Piotr Smolewski

Cancers 2022, 14(3), 771; https://doi.org/10.3390/cancers14030771 - 2 Feb 2022

Cited by 43 | Viewed by 6731

Abstract

The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKis are classified into two categories: irreversible (covalent) inhibitors [...] Read more.

The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKis are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors. Ibrutinib was the first irreversible BTK inhibitor approved by the U.S. Food and Drug Administration in 2013 as a breakthrough therapy in CLL patients. Subsequently, several studies have evaluated the efficacy and safety of new agents with reduced toxicity when compared with ibrutinib. Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, new reversible BTK inhibitors are currently under development in early-phase studies to improve their activity and to diminish adverse effects. This review summarizes the pharmacology, clinical efficacy, safety, dosing, and drug–drug interactions associated with the treatment of CLL with BTK inhibitors and examines their further implications. Full article

(This article belongs to the Special Issue Non-Hodgkin Lymphomas)

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17 pages, 1273 KiB

Open AccessReview

Recent Advances in the Diagnosis and Treatment of Natural Killer Cell Malignancies

by Eric Tse and Yok-Lam Kwong

Cancers 2022, 14(3), 597; https://doi.org/10.3390/cancers14030597 - 25 Jan 2022

Cited by 5 | Viewed by 3318

Abstract

Natural killer (NK)/T-cell lymphomas are aggressive malignancies. Epstein–Barr virus (EBV) infection in lymphoma cells is invariable. NK/T-cell lymphomas are divided into nasal, non-nasal, and disseminated subtypes. Nasal NK/T-cell lymphomas involve the nasal cavity and the upper aerodigestive tract. Non-nasal NK/T-cell lymphomas involve the [...] Read more.

Natural killer (NK)/T-cell lymphomas are aggressive malignancies. Epstein–Barr virus (EBV) infection in lymphoma cells is invariable. NK/T-cell lymphomas are divided into nasal, non-nasal, and disseminated subtypes. Nasal NK/T-cell lymphomas involve the nasal cavity and the upper aerodigestive tract. Non-nasal NK/T-cell lymphomas involve the skin, gastrointestinal tract, testis and other extranodal sites. Disseminated NK/T-cell lymphoma involves multiple organs, rarely presenting with a leukaemic phase. Lymphoma cells are positive for CD3ε (not surface CD3), CD56, cytotoxic molecules and EBV-encoded small RNA. There is a predilection for Asian and Central/South American populations. Genome-wide association studies have identified lymphoma susceptibility loci in Asian patients. Positron emission tomography computed tomography and plasma EBV DNA quantification are crucial evaluations at diagnosis and follow-up. Stage I/II patients typically receive non-athracycline regimens containing asparaginse, together with sequential/concurrent radiotherapy. Anthracycline-containing regimens are ineffective. Stage III/IV patients are treated with asparaginase-containing regimens, followed by allogeneic haematopoietic stem cell transplantation (HSCT) in suitable cases. Autologous HSCT does not improve outcome. In relapsed/refractory patients, novel approaches are needed, involving PD1/PD-L1 targeting, EBV-specific cytotoxic T-cells, and monoclonal antibodies. Small molecules including histone deacetylase inhibitors may be beneficial in selected patients. Future strategies may include targeting of signalling pathways and driver mutations. Full article

(This article belongs to the Special Issue Non-Hodgkin Lymphomas)

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24 pages, 10179 KiB

Open AccessReview

Primary Gastrointestinal T-Cell Lymphoma and Indolent Lymphoproliferative Disorders: Practical Diagnostic and Treatment Approaches

by Midori Filiz Nishimura, Yoshito Nishimura, Asami Nishikori, Tadashi Yoshino and Yasuharu Sato

Cancers 2021, 13(22), 5774; https://doi.org/10.3390/cancers13225774 - 18 Nov 2021

Cited by 15 | Viewed by 6634

Abstract

Primary gastrointestinal (GI) T-cell neoplasms are extremely rare heterogeneous disease entities with distinct clinicopathologic features. Given the different prognoses of various disease subtypes, clinicians and pathologists must be aware of the key characteristics of these neoplasms, despite their rarity. The two most common [...] Read more.

Primary gastrointestinal (GI) T-cell neoplasms are extremely rare heterogeneous disease entities with distinct clinicopathologic features. Given the different prognoses of various disease subtypes, clinicians and pathologists must be aware of the key characteristics of these neoplasms, despite their rarity. The two most common aggressive primary GI T-cell lymphomas are enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma. In addition, extranodal natural killer (NK)/T-cell lymphoma of the nasal type and anaplastic large cell lymphoma may also occur in the GI tract or involve it secondarily. In the revised 4th World Health Organization classification, indolent T-cell lymphoproliferative disorder of the GI tract has been incorporated as a provisional entity. In this review, we summarize up-to-date clinicopathological features of these disease entities, including the molecular characteristics of primary GI T-cell lymphomas and indolent lymphoproliferative disorders. We focus on the latest treatment approaches, which have not been summarized in existing reviews. Further, we provide a comprehensive review of available literature to address the following questions: How can pathologists discriminate subtypes with different clinical prognoses? How can primary GI neoplasms be distinguished from secondary involvement? How can these neoplasms be distinguished from non-specific inflammatory changes at an early stage? Full article

(This article belongs to the Special Issue Non-Hodgkin Lymphomas)

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