Selecting initial therapy in CLL.

Targeted therapy is a powerful treatment option in chronic lymphocytic leukemia (CLL) that has outperformed conventional chemoimmunotherapy in most clinical settings. Except for selected young, fit patients with a mutated immunoglobulin heavy chain variable region gene, most patients benefit from targeted therapy with either a continuous BTK inhibitor or 1-year fixed-duration venetoclax-obinutuzumab as first-line treatment of CLL. Treatment selection is driven by patient-, treatment-, and disease-related factors, encompassing patient preference, concomitant medications, comorbidities, safety profile of the regimen, and TP53 aberration. Clinical trials are actively investigating the simultaneous inhibition of Bruton's tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) proteins with or without a CD20 monoclonal antibody, which can achieve deep response in most patients (52%-89% undetectable minimal residual disease in bone marrow).

[Warm autoimmune hemolytic anemia and IgM-monoclonal gammopathy following BNT162b2 COVID-19 vaccine in a patient with splenic marginal zone lymphoma].

There is currently no evidence that a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine might be associated with the development of autoimmune hemolytic anemia or disease progression in patients with mature B-cell neoplasm. Our patient was a 71-year-old man with indolent mature B-cell neoplasm who had been monitored for many years without treatment. After receiving the second dose of the BNT162b2 mRNA COVID-19 vaccine, he developed severe warm autoimmune hemolytic anemia. Although steroid therapy improved his anemia, he continued to develop IgM-monoclonal gammopathy, renal insufficiency, and splenomegaly. He was diagnosed with splenic marginal zone lymphoma after undergoing splenectomy. The splenectomy improved the patient's symptoms. We assessed his SARS-CoV-2 specific antibody response, but the patient's serologic response to the vaccine was impaired. In patients with mature B-cell neoplasm, a non-specific immune response after vaccination might be associated with paraneoplastic syndromes.

Chinese expert consensus on oral drugs for the treatment of mature B-cell lymphomas (2020 edition).

Oral drugs such as ibrutinib play an important role in the treatment of mature B-cell lymphoma (BCL) due to their reliable efficacy, manageable safety, high accessibility, and convenience for use. Still, no guidelines or consensus focusing on oral drug therapies for BCL is available. To provide a reference of oral agent-based treatment for mature BCL, a panel of experts from the Lymphocyte Disease Group, Chinese Society of Hematology, Chinese Medical Association conducted an extensive discussion and reached a consensus on oral drugs for Chinese BCL patients on the basis of the current application status of oral drugs in China, combined with the latest authoritative guidelines in the world and current research reports. This consensus reviewed the application of oral drugs in the treatment of BCL and the latest research and provided appropriate recommendations on the use of oral drugs for indolent or aggressive BCL patients. With the deepening of research and the development of standardized clinical applications, oral medications will bring better treatment to BCL patients, enabling more patients to benefit from them.

Safety and efficacy of a dose-dense short-term therapy in patients with MYC-translocated aggressive lymphoma.

Patients with aggressive B-cell lymphoma and MYC rearrangement at fluorescence in situ hybridization exhibit poor outcome after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). In the last decade, 68 patients with Burkitt lymphoma ([BL] n = 46) or high-grade B-cell lymphoma ([HGBCL] single, double, or triple hit; n = 22) were treated with a dose-dense, short-term therapy termed "CARMEN regimen" at 5 Italian centers. Forty-six (68%) patients were HIV+. CARMEN included a 36-day induction with sequential, single weekly doses of cyclophosphamide, vincristine, rituximab, methotrexate, etoposide, and doxorubicin plus intrathecal chemotherapy, followed by high-dose-cytarabine-based consolidation. Patients who did not achieve complete remission (CR) after induction received BEAM (carmustina, etoposide, cytarabine, melfalan)-conditioned autologous stem cell transplantation (ASCT) after consolidation. Sixty-one (90%) patients completed induction, and 59 (87%) completed consolidation. Seventeen patients received ASCT. Grade 4 hematological toxicity was common but did not cause treatment discontinuation; grade 4 nonhematological toxicity was recorded in 11 (16%) patients, with grade 4 infections in 6 (9%). Six (9%) patients died of toxicity (sepsis in 4, COVID-19, acute respiratory distress syndrome). CR rate after the whole treatment was 73% (95% confidence interval [CI], 55% to 91%) for patients with HGBCL and 78% (95% CI, 66% to 90%) for patients with BL. At a median follow-up of 65 (interquartile range, 40-109) months, 48 patients remain event free, with a 5-year progression-free survival of 63% (95% CI, 58% to 68%) for HGBCL and 72% (95% CI, 71% to 73%) for BL, with a 5-year overall survival (OS) of 63% (95% CI, 58% to 68%) and 76% (95% CI, 75% to 77%), respectively. HIV seropositivity did not have a detrimental effect on outcome. This retrospective study shows that CARMEN is a safe and active regimen both in HIV-negative and -positive patients with MYC-rearranged lymphomas. Encouraging survival figures, attained with a single dose of doxorubicin and cyclophosphamide, deserve further investigation in HGBCL and other aggressive lymphomas.

Persistence of SARS-CoV-2 Infection in Severely Immunocompromised Patients With Complete Remission B-Cell Lymphoma and Anti-CD20 Monoclonal Antibody Therapy: A Case Report of Two Cases.

Immunosuppressant conditions such as hematological malignancies increase the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It has been described in the literature that patients on anti-CD20 maintenance therapies for lymphoid malignancies are susceptible to having recurrent flares together with viral replication or reinfections, although these cases are scarce. These patients are not well represented in randomized controlled trials, and as a consequence, the evidence for the use of certain treatments in this scenario is lacking. We present two cases of patients with B-cell lymphoma on remission and treated with rituximab on maintenance. They developed at least 1 flare of coronavirus disease 2019 (COVID-19) after acute infection and always after receiving rituximab. RT-PCR was positive in the nasopharyngeal swab and also in plasma. Patients were treated during flares with remdesivir, hyperimmune plasma, and corticosteroids. These two cases showed the unresolved problem of COVID-19 in immunosuppressant patients and showed that despite the vast amount of information available on SARS-CoV-2, information in this subgroup of patients is lacking.

Limited increase in antibody titers following mRNA SARS-CoV-2 vaccination for more than 3 years after final dose of anti-CD20 antibody.

We investigated the efficacy of BNT162b2 mRNA COVID-19 vaccine in patients with B-cell malignancies treated with anti-CD20 antibody. Although T-cell-mediated immune responses were detected even in patients receiving R-CHOP treatment, the S1 antibody titer following BNT162b2 vaccination remained only marginally increased for more than 3 years after the final dose of anti-CD20 antibody. We found no relationship between the percent of B-cells and S1 antibody titer. The duration of this suppression was much longer than we anticipated. Further protection and treatment strategies against COVID-19 for these patients are warranted.

Complete response in a frail patient with high-grade B-cell lymphoma to only one cycle of R-CHOP or to prolonged COVID-19?

BACKGROUND: COVID-19 infection increases mortality in hematological malignancies. In a large meta-analysis, patients aged 60 years and older had a significantly higher risk of death than patients under 60 years of age [1]. Furthermore, a high risk of death and reduced survival in patients receiving B cell depletion therapy with prolonged COVID-19 infection was reported in a recent study [2]. High-grade B-cell lymphomas are classified as morphologically aggressive lymphomas with the presence of a high mitotic index and Ki-67 proliferation rates. They demonstrate aggressive behavior clinically as well as morphologically, and COVID-19 infection is an important factor that increases mortality in these patients. Herein, we present an elderly patient with a diagnosis of high-grade B-cell lymphoma, in whom a complete response was observed after prolonged COVID-19 infection. CASE SUMMARY: An 81-year-old female patient received her first cycle of R-CHOP (rituximab, cyclophosphamide, vincristine, and prednisolone) treatment after being diagnosed with high- grade B-cell lymphoma. After being discharged from the hospital, the patient was referred to the emergency department with complaints of fever and fatigue when she came for the second cycle of chemotherapy. Her COVID-19 PCR test was found positive. She was admitted to the infectious diseases service and favipiravir treatment was started. On the 24th day of hospitalization, it was decided to perform interim FDG-PET/CT (Fluorodeoxyglucose - Positron Emission Tomography/Computed Tomography) scan at a time that her PCR (Polymerase Chain Reaction) test was still positive. A complete metabolic response was detected in her imaging. On the 26th day, the PCR test became negative and the patient was transferred to the oncology service and received the second cycle of R-CHOP treatment. CONCLUSION: Our case emphasizes that antitumor effect could be seen in a patient with SARS-CoV-2 infection and a hematologic malignancy. It also highlights being alert to prolonged COVID-19 infection in patients receiving B-cell depletion therapy.

Successful treatment of COVID-19 infection with convalescent plasma in B-cell-depleted patients may promote cellular immunity.

Treatment with convalescent plasma has been shown to be safe in coronavirus disease in 2019 (COVID-19) infection, although efficacy reported in immunocompetent patients varies. Nevertheless, neutralizing antibodies are a key requisite in the fight against viral infections. Patients depleted of antibody-producing B cells, such as those treated with rituximab (anti-CD20) for hematological malignancies, lack a fundamental part of their adaptive immunity. Treatment with convalescent plasma appears to be of general benefit in this particularly vulnerable cohort. We analyzed clinical course and inflammation markers of three B-cell-depleted patients suffering from COVID-19 who were treated with convalescent plasma. In addition, we measured serum antibody levels as well as peripheral blood CD38/HLA-DR-positive T-cells ex vivo and CD137-positive T-cells after in vitro stimulation with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides in these patients. We observed that therapy with convalescent plasma was effective in all three patients and analysis of CD137-positive T-cells after stimulation with SARS-CoV-2 peptides showed an increase in peptide-specific T-cells after application of convalescent plasma. In conclusion, we here demonstrate efficacy of convalescent plasma therapy in three B-cell-depleted patients and present data that suggest that while application of convalescent plasma elevates systemic antibody levels only transiently, it may also boost specific T-cell responses.

Usefulness of Plasma SARS-CoV-2 RNA Quantification by Droplet-based Digital PCR to Monitor Treatment Against COVID-19 in a B-cell Lymphoma Patient.

We report the case of an HIV-1-infected patient, treated with anti-CD20 monoclonal antibody for a B-cell lymphoma previously treated by autologous stem cell transplant. He suffered from chronic COVID19 and we monitored by plasma SARS-CoV-2 RNA by highly sensitive droplet-based digital PCR technology (ddPCR). Under tocilizumab therapy and despite a first clinical improvement biologically associated with decreasing inflammatory markers, a slight increase of SARS-CoV-2 RNAaemia quantified by ddPCR was highlighted, confirming the absence of viral efficacy of this treatment and predicting the subsequent observed deterioration. As expected, his complete recovery, finally achieved after COVID-19 convalescent plasmatherapy, strictly paralleled plasma SARS-CoV-2 RNA clearance. With these results, we confirmed the interest of SARS-CoV-2 RNAaemia monitoring by ddPCR in COVID-19 patients, particularly during treatment, and firstly showed that this new and specific biomarker could be helpful to select eligible patient for anti-IL6 receptors therapy considering the variable levels of efficacy recently observed with such therapy.

BTK Inhibitors in Cancer Patients with COVID-19: "The Winner Will be the One Who Controls That Chaos" (Napoleon Bonaparte).

As the SARS-CoV-2 (COVID-19) pandemic spreads and the number of Bruton's tyrosine kinase inhibitor (BTKi)-treated COVID-19-affected patients grows, we must consider the pros and cons of BTKi discontinuation for our patients. In favor of BTKi continuation, BTK plays an active role in macrophage polarization. By modulating key transcription factors, BTK may regulate macrophage polarization downstream of classic M1 and M2 polarizing stimuli and mitigate the hyperinflammatory state associated with COVID-19. In favor of BTKi discontinuation, we note a potentially increased risk of secondary infections and impaired humoral immunity. We hypothesize that the potential benefit of blunting a hyperinflammatory response to SARS-CoV-2 through attenuation of M1 polarization outweighs the potential risk of impaired humoral immunity, not to mention the risk of rapid progression of B-cell malignancy following BTKi interruption. On the basis of this, we suggest continuing BTKi in patients with COVID-19.