Anaplastic Large-Cell Lymphoma (ALCL) First Manifested as a Rapidly Progressive Acute Respiratory Failure (RF): Lymph Node Biopsy Negative Presentation Posing a Diagnostic Challenge.

Anaplastic large-cell lymphoma (ALCL) is an aggressive subtype of non-Hodgkin lymphoma. There are two forms of ALCL: primary and secondary. Primary can be systemic, affecting multiple organs, or cutaneous, affecting mainly the skin. A secondary form occurs when another lymphoma undergoes an anaplastic transformation. ALCL rarely presents as initial symptoms of respiratory failure. In most of these situations, the trachea or bronchial involved with an obstruction was present. We present an unusual case of ALCL where the patient rapidly progressed to acute hypoxic respiratory failure with a patent bronchus and trachea. Unfortunately, the patient rapidly deteriorated and died before diagnosis. Only upon at autopsy, it was found that his lung parenchyma was diffusely involved with ALCL. The autopsy report showed that the patient had CD-30 anaplastic lymphoma kinase (ALK)-negative ALCL diffusely involving all lung fields.

Infectious complications following CAR-t cell therapy for B cell non-Hodgkin lymphoma: a single-center experience and review of the literature.

Chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed (R/R) B-cell non-Hodgkin lymphoma (NHL). Several risk factors including CAR-T cell-related toxicities and their treatments often lead to infectious complications (ICs); however, the pattern and timeline is not well established. We evaluated ICs in 48 patients with R/R B-cell NHL following CAR-T cell therapy at our institution. Overall, 15 patients experienced 22 infection events. Eight infections (4 bacterial, 3 viral and 1 fungal) occurred within the first 30 days and 14 infections (7 bacterial, 6 viral, 1 fungal) between days 31 to 180 following CAR-T infusion. Most infections were mild-to-moderate and fifteen infections involved the respiratory tract. Two patients developed mild-to-moderate COVID-19 infection and one patient a cytomegalovirus reactivation after CAR-T infusion. Two patients developed IFIs: one case each of fatal disseminated candidiasis and invasive pulmonary aspergillosis at day 16 and 77, respectively. Patients with more than 4 prior antitumor regimens and patient's ≥ 65 years had a higher infection rate. Infections in patients with relapsed/refractory B-cell NHL are common after CAR-T despite the use of infection prophylaxis. Age ≥ 65 years and having > 4 prior antitumor treatments were identified as risk factors for infection. Fungal infections carried significant impact in morbidity and mortality, suggesting a role for increase fungal surveillance and/or anti-mold prophylaxis following high-dose steroids and tocilizumab. Four of ten patients developed an antibody response following two doses of SARS-CoV-2 mRNA vaccine.

INTERIM RESULTS OF THE PML-16, PML-19 PROTOCOLS FOR PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA THERAPY

Introduction. Primary mediastinal lymphoma (PML) is an aggressive lymphoid tumor treatment success of which is determined by induction therapy. To date, none of the standard chemotherapy regimens (CT) have demonstrated an advantage in efficacy. Intensive therapy programs are associated with high toxicity. Aim - to evaluate the efficacy and toxicity of two pilot prospective treatment protocols PML-16 and PML-19 as well as the possibility of using the analysis of freely circulating tumor DNA (ctDNA) to assess MRD in patients with PML. Materials and methods. From January 2016 to January 2022, 34 previously untreated PML patients were included in the study;average age - 32;stage > I - in 60 %;extramediastinal lesions - in 14.7 %;bulky disease - in 73.5 % of patients. Positron emission tomography combined with computed tomography (PET-CT) was performed;ctDNA was determined to assess the completeness of remission. Results. Eighteen patients received treatment according to the PML-16 protocol (6 courses of chemotherapy;2 blocks of RmNHL-BFM-90 + 4 courses of R-EPOCH). After the end of therapy, all 18 patients achieved PET-negative remission. The next 16 patients received treatment according to the PML-19 protocol (4 courses of chemotherapy;2 blocks of R-mNHL-BFM-90 + 2 courses of R-EPOCH) in combination with lenalidomide. After the end of therapy, 9 (56 %) patients achieved PET-negative remission;7 (44 %) retained pathological activity (D4-5 points). After 3 and 6 months 15 (94 %) patients achieved normalization of metabolic activity. Considering the high frequency of false-positive results in patients with PML, a ctDNA study was performed to determine the depth of remission in 15 patients. After the end of therapy, all 15 patients had complete elimination of ctDNA. Of these, 5 (33 %) remained PET-positive at the end of treatment. During further observation, after 3-6 months, in 4 patients the level of metabolic activity decreased to physiological without the use of consolidating therapy. After the end of therapy, one patient suffered the new coronavirus infection, COVID-19. A month later, residual formation of SUVmax 14.2 remained in the mediastinum. The patient is currently under observation. With a median follow-up of 36 months (9 to 76 months) all 34 patients are in remission. Conclusion. The effectiveness of PML-16 made it possible to abandon the consolidation therapy and refuted the idea of the need for 6 courses of CT. The combination of programs based on the application of the principle of high-dose short-pulse induction of remission (R-mNHL-BFM-90) in combination with the prolonged administration of medium doses (R-EPOCH) was crucial in achieving a successful result. The inclusion of lenalidomide in the "PML-19" program made it possible to achieve complete remission in 100 % of cases after 4 courses. The possibility of using DNA analysis to assess MRD in patients with PML was shown.Copyright © 2022 Izdatel'stvo Meditsina. All rights reserved.

INTERIM RESULTS OF THE PML-16, PML-19 PROTOCOLS FOR PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA THERAPY.

Introduction. Primary mediastinal lymphoma (PML) is an aggressive lymphoid tumor treatment success of which is determined by induction therapy. To date, none of the standard chemotherapy regimens (CT) have demonstrated an advantage in efficacy. Intensive therapy programs are associated with high toxicity. Aim - to evaluate the efficacy and toxicity of two pilot prospective treatment protocols PML-16 and PML-19 as well as the possibility of using the analysis of freely circulating tumor DNA (ctDNA) to assess MRD in patients with PML. Materials and methods. From January 2016 to January 2022, 34 previously untreated PML patients were included in the study;average age - 32;stage > I - in 60 %;extramediastinal lesions - in 14.7 %;bulky disease - in 73.5 % of patients. Positron emission tomography combined with computed tomography (PET-CT) was performed;ctDNA was determined to assess the completeness of remission. Results. Eighteen patients received treatment according to the PML-16 protocol (6 courses of chemotherapy;2 blocks of RmNHL-BFM-90 + 4 courses of R-EPOCH). After the end of therapy, all 18 patients achieved PET-negative remission. The next 16 patients received treatment according to the PML-19 protocol (4 courses of chemotherapy;2 blocks of R-mNHL-BFM-90 + 2 courses of R-EPOCH) in combination with lenalidomide. After the end of therapy, 9 (56 %) patients achieved PET-negative remission;7 (44 %) retained pathological activity (D4-5 points). After 3 and 6 months 15 (94 %) patients achieved normalization of metabolic activity. Considering the high frequency of false-positive results in patients with PML, a ctDNA study was performed to determine the depth of remission in 15 patients. After the end of therapy, all 15 patients had complete elimination of ctDNA. Of these, 5 (33 %) remained PET-positive at the end of treatment. During further observation, after 3-6 months, in 4 patients the level of metabolic activity decreased to physiological without the use of consolidating therapy. After the end of therapy, one patient suffered the new coronavirus infection, COVID-19. A month later, residual formation of SUVmax 14.2 remained in the mediastinum. The patient is currently under observation. With a median follow-up of 36 months (9 to 76 months) all 34 patients are in remission. Conclusion. The effectiveness of PML-16 made it possible to abandon the consolidation therapy and refuted the idea of the need for 6 courses of CT. The combination of programs based on the application of the principle of high-dose short-pulse induction of remission (R-mNHL-BFM-90) in combination with the prolonged administration of medium doses (R-EPOCH) was crucial in achieving a successful result. The inclusion of lenalidomide in the "PML-19" program made it possible to achieve complete remission in 100 % of cases after 4 courses. The possibility of using DNA analysis to assess MRD in patients with PML was shown.Copyright © 2022 Izdatel'stvo Meditsina. All rights reserved.

Anti-CD20 antibodies and bendamustine attenuate humoral immunity to COVID-19 vaccination in patients with B-cell non-Hodgkin lymphoma.

Serologic responses of COVID-19 vaccine are impaired in patients with B-cell lymphoma, especially those who had recently been treated with anti-CD20 monoclonal antibodies. However, it is still unclear whether those patients develop an immune response following vaccination. We investigated the efficacy of vaccination against SARS-CoV-2 in 171 patients with B-cell non-Hodgkin lymphoma (B-NHL) who received two doses of an mRNA-based COVID-19 vaccine and we compared the efficacy of vaccination to that in 166 healthy controls. Antibody titers were measured 3 months after administration of the second vaccine dose. Patients with B-NHL showed a significantly lower seroconversion rate and a lower median antibody titer than those in healthy controls. The antibody titers showed correlations with the period from the last anti-CD20 antibody treatment to vaccination, the period from the last bendamustine treatment to vaccination and serum IgM level. The serologic response rates and median antibody titers were significantly different between diffuse large B-cell lymphoma (DLBCL) patients in whom anti-CD20 antibody treatment was completed within 9 months before vaccination and follicular lymphoma (FL) patients in whom anti-CD20 antibody treatment was completed within 15 months before vaccination. Moreover, the serologic response rates and median antibody titers were significantly different among FL patients in whom bendamustine treatment was completed within 33 months before vaccination. We demonstrated that B-NHL patients who were recently treated with anti-CD20 antibodies and bendamustine had a diminished humoral response to COVID-19 vaccination. UMIN 000,045,267.

The impact of COVID-19 on national hockey league players' return to play.

OBJECTIVE: Evaluate the on-ice performance and return to play (RTP) rate following COVID-19 for National Hockey League (NHL) players during the 2020-21 season. METHODS: Players with COVID-19 during the abbreviated 2020-21 season were identified using publicly accessible online sources. Demographics and on-ice metrics were accessed using the NHL's online statistics website. The length of time, rate of RTP, and games missed due to COVID-19 were analyzed. Primary outcomes included average time on ice (TOI) per game (TOI/G), average TOI per shift (TOI/S), and points per game (PPG) compared at different timepoints including pre- and post-COVID-19. RESULTS: A total of 73 players (47 forwards, 18 defensemen, 8 goalies) had a documented COVID-19 diagnosis during the abbreviated 2020-21 season. Players missed an average of 5.6 games (14.7 days) due to COVID-19. The post-COVID-19 RTP rate was 97.3%, including playoffs. No differences were found in TOI/G between the pre- (15.7 ± 3.9 min) and post-COVID-19 (15.8 ± 3.4 min, p = 0.874) or in the first (15.8 ± 4.0 min) and second week (15.9 ± 3.8 min, p = 0.925) returned. TOI/shift did not change from pre- (45.6 ± 5.3 sec) to post-COVID-19 (46.7 ± 4.6 sec, p = 0.035) or in first (46.2 ± 5.4 sec) and second week post-COVID-19 (46.2 ± 4.8 sec, p = .854). No differences were identified for PPG between career, pre-COVID-19, and post-COVID-19 (0.44 vs 0.38 vs 0.41; p = 0.274). CONCLUSION: RTP post-COVID was markedly high for NHL players. While the effects of COVID-19 on specific physiological measures remains to be elucidated, this study found NHL players do not have reduced performance following COVID-19.

Interim Results of the Pml-16, Pml-19 Protocols for Primary Mediastinal Large B-Cell Lymphoma Therapy

Introduction. Primary mediastinal lymphoma (PML) is an aggressive lymphoid tumor treatment success of which is determined by induction therapy. To date, none of the standard chemotherapy regimens (CT) have demonstrated an advantage in efficacy. Intensive therapy programs are associated with high toxicity. Aim - to evaluate the efficacy and toxicity of two pilot prospective treatment protocols PML-16 and PML-19 as well as the possibility of using the analysis of freely circulating tumor DNA (ctDNA) to assess MRD in patients with PML. Materials and methods. From January 2016 to January 2022, 34 previously untreated PML patients were included in the study;average age - 32;stage > I - in 60 %;extramediastinal lesions - in 14.7 %;bulky disease - in 73.5 % of patients. Positron emission tomography combined with computed tomography (PET- CT) was performed;ctDNA was determined to assess the completeness of remission. Results. Eighteen patients received treatment according to the PML-16 protocol (6 courses of chemotherapy;2 blocks of R-mNHL-BFM-90 + 4 courses of R-EPOCH). After the end of therapy, all 18 patients achieved PET-negative remission. The next 16 patients received treatment according to the PML-19 protocol (4 courses of chemotherapy;2 blocks of R-mNHL-BFM-90 + 2 courses of R-EPOCH) in combination with lenalidomide. After the end of therapy, 9 (56 %) patients achieved PET-negative remission;7 (44 %) retained pathological activity (D4-5 points). After 3 and 6 months 15 (94 %) patients achieved normalization of metabolic activity. Considering the high frequency of false-positive results in patients with PML, a ctDNA study was performed to determine the depth of remission in 15 patients. After the end of therapy, all 15 patients had complete elimination of ctDNA. Of these, 5 (33 %) remained PET-positive at the end of treatment. During further observation, after 3-6 months, in 4 patients the level of metabolic activity decreased to physiological without the use of consolidating therapy. After the end of therapy, one patient suffered the new coronavirus infection, COVID-19. A month later, residual formation of SUVmax 14.2 remained in the mediastinum. The patient is currently under observation. With a median follow-up of 36 months (9 to 76 months) all 34 patients are in remission. Conclusion. The effectiveness of PML-16 made it possible to abandon the consolidation therapy and refuted the idea of the need for 6 courses of CT. The combination of programs based on the application of the principle of high-dose short-pulse induction of remission (R-mNHL-BFM-90) in combination with the prolonged administration of medium doses (R-EPOCH) was crucial in achieving a successful result. The inclusion of lenalidomide in the "PML-19" program made it possible to achieve complete remission in 100 % of cases after 4 courses. The possibility of using DNA analysis to assess MRD in patients with PML was shown.

Global reported impacts of COVID-19 on lymphoma patients and the emerging clinical management approaches in response to the ongoing pandemic.

The Coronavirus disease 2019 (COVID-19) pandemic has dramatically impacted the health risk and management of patients with lymphoma. Clinical evaluations on the impact of COVID-19 on lymphoma patients are currently limited however, reports have shown a correlation with specific variants and more severe COVID-19 complications and higher mortality rates relative to other disease states and age-matched populations. During peak pandemic periods this created a concerning management problem for clinicians and raised the question of how different immunocompromised states increase COVID-19-associated risk and provided insights into how immunity interacts with the circulating variant, including the effects of low virulent variants in vaccinated lymphoma populations. Treatment management approaches, polymerase chain reaction tests and rapid antigen screening guidelines have been offered in an attempt to reduce the risk of harm to lymphoma patients, particularly prior to and following bone marrow or stem cell transplant. Here we systematically review the current literature to provide a novel global perspective on incidence, mortality, management and rapid antigen test (RAT) screening for COVID-19, in patients with various subtypes of lymphoma. Furthermore, lessons learned from emerging variants that continue to inform evolving lymphoma management and public health policies are addressed across these associated matters.

B-cell malignancies treated with targeted drugs and SARS-CoV-2 infection: A European Hematology Association Survey (EPICOVIDEHA).

Patients with lymphoproliferative diseases (LPD) are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we describe and analyze the outcome of 366 adult patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin Lymphoma (NHL) treated with targeted drugs and laboratory-confirmed COVID-19 diagnosed between February 2020 and January 2022. Median follow-up was 70.5 days (IQR 0-609). Most used targeted drugs were Bruton-kinase inhibitors (BKIs) (N= 201, 55%), anti-CD20 other than rituximab (N=61, 16%), BCL2 inhibitors (N=33, 9%) and lenalidomide (N=28, 8%).Only 16.2% of the patients were vaccinated with 2 or more doses of vaccine at the onset of COVID-19. Mortality was 24% (89/366) on day 30 and 36%(134/366) on the last day of follow-up. Age >75 years (p<0.001, HR 1.036), active malignancy (p<0.001, HR 2.215), severe COVID-19 (p=0.017, HR 2.270) and admission to ICU (p<0.001, HR 5.751) were risk factors for mortality at last day of follow up. There was no difference in OS rates in NHL vs CLL patients (p=0.306), nor in patients treated with or without BKIs (p=0.151). Mortality in ICU was 66% (CLL 61%, NHL 76%). Overall mortality rate decreased according to vaccination status, being 39% in unvaccinated patients, 32% and 26% in those having received one or two doses, respectively, and 20% in patients with a booster dose (p=0.245). Overall mortality rate dropped from 41% during the first semester of 2020 to 25% at the last semester of 2021. These results show increased severity and mortality from COVID-19 in LPDs patients treated with targeted drugs.

How to prioritize treatment in dual malignancy: A case report of patient with non-Hodgkin lymphoma and breast cancer.

Introduction: Clinicians often encounter dilemma upon treating multiple primary malignancies. Case presentation: We report a case of a female patient, 72, complained of a lump under her left eye since January 2019. Patient was diagnosed with infiltrating ductal carcinoma grade III of the right breast in June 2018 with ER+, PR+, and HER2-, treated with hormonal treatment. Histopathology examination of the lump revealed Non Hodgkin Lymphoma (NHL), B cell type, high grade. Patients received rituximab, cyclophosphamide, epirubicin, vincristin, and prednisone (RHCOP) for 6 cycles to overcome lymphoma then received hormonal therapy afterwards. Clinical discussion: According to earlier published case reports, it's advised to start hormonal therapy after RHCOP. The survival time was 21 months (5.1-114.7 months) with 5-year overall survival 29. Conclusion: Unfortunately, we could not have a follow-up on the patient after finishing 6 cycles of RHCOP due to the COVID-19 pandemic situation.

Higher mortality of hospitalized haematologic patients with COVID-19 compared to non-haematologic is driven by thrombotic complications and development of ARDS: An age-matched cohorts study.

BACKGROUND AND OBJECTIVES: The characteristics of COVID-19 in haematologic patients compared to non-haematologic patients have seldom been analyzed. Our aim was to analyze whether there are differences in clinical characteristics and outcome of haematologic patients with COVID-19 as compared to non-haematologic. PATIENTS AND METHODS: Retrospective cohort study in 2 University hospitals of patients admitted with laboratory-confirmed COVID-19 included in the SEMICOVID19 database. The cohort with underlying haematologic disease was compared to a cohort of age and date-of-COVID-19-matched controls without haematologic disease (1:2). RESULTS: 71 cases and 142 controls were included from March-May 2020.Twenty (28.1%) had received recent chemotherapy. Twelve (16.9%) were stem cell transplant recipients (SCT). Eleven (15.5%) were neutropenic concurrently with COVID-19 diagnosis.Haematologic patients presented ARDS (58.5 vs 20.7%, p = 0.0001), thrombotic complications (15.7 vs 2.1%, p = 0.002), DIC (5.7 vs 0.0%, p = 0.011), heart failure (14.3 vs 4.9%, p = 0.029) and required ICU admission (15.5 vs 2.8%, p = 0.001), MV (14.1% vs 2.1%, p 0.001), steroid (64.8 vs 33.1%, p = 0.0001), tocilizumab (33.8 vs 8.5%, p = 0.0001) or anakinra treatment (9.9% vs 0%, p = 0.0001) more often. In-hospital mortality was significantly higher (38.0% vs 18.3%, p = 0.002). CONCLUSIONS: Our results suggest COVID-19 has worse outcomes in haematologic patients than in non-haematologic, independently of age, and that the development of ARDS and thrombotic complications drive the higher in-hospital mortality.

Epidemiology of Food Insecurity in a Nationally Representative Sample of Lymphoma Patients.

BACKGROUND: In 2020, the United States had approximately 85,000 new diagnoses of Hodgkin and Non-Hodgkin lymphoma. Food insecurity is both a direct and indirect detriment to health outcomes. The rate and risk factors for food insecurity among lymphoma patients are unknown, as the unemployment rate soars far above pre-COVID19 pandemic levels further heightening the economic stresses of a lymphoma diagnosis. METHODS: Data regarding the food security status were obtained from the cross-sectional National Health Interview Survey (NHIS) conducted by the Centers for Disease Control and Prevention. A raw score compiled from a series of 10 food security questions was used to determine the Food Secure and Food Insecure groups. Respondents who reported a history of lymphoma from 2011 to 2019 were included in the analysis. RESULTS: Of the 921 patients reporting a history of lymphoma 9.06% were considered Food Insecure. The sociodemographic subgroups with the highest risk of being Food Insecure included respondents living below 100% of the Federal Poverty Level, non-US citizens, the uninsured, and those on Medicare. CONCLUSION: Food insecurity is common among lymphoma patients. Therefore, oncologists across the country should be aware of the sociodemographic risk factors for food insecurity in order to assist in mediation, maximizing the efficacy of treatments. Research regarding the impact of food insecurity on therapy compliance and patient outcomes is warranted in future studies.

HBV Reactivation During the Treatment of Non-Hodgkin Lymphoma and Management Strategies.

Hepatitis B virus reactivation (HBV-R), which can lead to HBV-related morbidity and mortality, is a common and well-known complication that occurs during the treatment of non-Hodgkin lymphoma (NHL) patients with current or past exposure to HBV infection. HBV-R is thought to be closely associated with chemotherapeutic or immunosuppressive therapies. However, immunosuppressive agents such as anti-CD20 antibodies (e.g., rituximab and ofatumumab), glucocorticoids, and hematopoietic stem cell transplantation (HSCT) administered to NHL patients during treatment can cause deep immunodepression and place them at high risk of HBV-R. In this review, we explore the current evidence, the guidelines of several national and international organizations, and the recommendations of expert panels relating to the definition, risk factors, screening and monitoring strategies, whether to use prophylaxis or pre-emptive therapy, and the optimal antiviral agent and duration of antiviral therapy for HBV-R.

How Fear of COVID-19 Can Affect Treatment Choices for Anaplastic Large Cell Lymphomas ALK+ Therapy: A Case Report.

BACKGROUND: The t (2; 5) chromosomal rearrangement of the ALK gene with nucleophosmin 1 gene (NPM1), resulting in an NPM1-ALK fusion, was first demonstrated in 1994 in anaplastic large cell lymphoma, (ALCL), a T-cell lymphoma responsive to cyclophosphamide, abriblastine, vincristine and prednisone in approximately 80% of cases; refractory cases usually respond favorably to brentuximab vedotin. These treatments are regarded as a bridge to allogeneic hematopoietic stem cell transplantation (allo-SCT). Nowadays, transplant procedures and the monitoring of chemotherapy patients proceed very slowly because the SARS-CoV-2 pandemic has heavily clogged the hospitals in all countries. RESULTS: A 40-year-old Caucasian woman was first seen at our clinical center in June 2020. She had ALCL ALK+, a history of failure to two previous therapeutic lines and was in complete remission after 12 courses of brentuximab, still pending allo-SCT after two failed donor selections. Facing a new therapeutic failure, we requested and obtained authorization from the Italian drug regulatory agency to administer 250 mg of crizotinib twice a day, a drug incomprehensibly not registered for ALCL ALK +. CONCLUSIONS: The response to crizotinib was optimal since no adverse event occurred, and CT-PET scans persisted negative; this drug has proved to be a valid bridge to allo-SCT.

Prolonged Course of COVID-19-Associated Pneumonia in a B-Cell Depleted Patient After Rituximab.

Patients with pre-existing comorbidities and immunosuppression are at greater risk for SARS-CoV-2 infection and severe manifestations of COVID-19. This also includes cancer patients, who are shown to have a poor prognosis after infection. Here, we describe the case of a 72-year old male patient with B-cell depletion after maintenance treatment with rituximab for non-Hodgkin-lymphoma who had a prolonged COVID-19 course and initial false negative test results. Our case highlights the diagnostic pitfalls in diagnosing COVID-19 in B-cell depleted patients and discuss the role of B-cell depletion in the course and treatment of COVID-19. Furthermore, we investigated peripheral blood monocytes and SARS-CoV-2 specific T cells in our patient. In conclusion, our case report can help physicians to avoid diagnostic pitfalls for COVID-19 in hemato-oncological patients under chemoimmunotherapy and tries to explain the role of B-cell depletion and SARS-CoV-2 specific T cells in this context.