ABSTRACT
Background: Patients with hematological malignancies are at a higher risk of developing severe form and protracted course of COVID-19. Remdesivir, an inhibitor of RNA polymerase was identified early as a promising therapeutic regimen for COVID-19, while convalescent plasma (CP) therapy with anti-SARS-CoV-2 antibodies can aid the treatment of COVID-19 in B-cell depleted patients. Aims: Here we investigated whether the combination of externally administered immunoglobulins (Ig) via CP therapy and specific inhibition of viral replication might be sufficient to effectively treat B-cell depleted patients with COVID-19. Methods: We enrolled a series of 20 consecutive patients who suffered from various hematological malignancies with profound B-cell lymphopenia and COVID-19 pneumonia between December 2020 and May 2021. These patients demonstrated a profound B-cell lymphopenia based on flow cytometry analysis of peripheral blood lymphocyte subpopulations. Consequently, they showed undetectable baseline anti-SARS-CoV-2 Ig levels before CP therapy according to anti-SARS-CoV-2 nucleocapsid-and S1-RBD-specific total Ig tests. Each patient received a complete course of remdesivir and at least one unit (200 ml) of AB0 compatible convalescent plasma during their treatment for COVID-19. Results: Previous anti-CD20 therapy resulted in a more prolonged SARS-CoV-2 PCR positivity compared to other causes of Bcell lymphopenia (p=0.004). Timing of CP therapy showed a significant impact on the clinical outcome. Simultaneous use of remdesivir and CP reduced time period for oxygen weaning after diagnosis (p=0.017), length of hospital stay (p=0.007), and PCR positivity (p=0.012) compared to patients who received remdesivir and CP consecutively. In addition, time from the diagnosis to CP therapy affected the length of oxygen dependency (p<0.001) and hospital stay (p<0.0001). In those cases where there were at least ten days from the diagnosis to plasma administration, oxygen dependency was prolonged vs. patients with shorter interval (p<0.001). Summary/Conclusion: Via combined administration of remdesivir and CP, we experienced an overwhelming survival rate in COVID-19 patients with hematological malignancies. Inhibition of viral replication with passive immunization proved to be efficient and safe. Our results suggest the clear benefit of early administration of CP to avoid protracted COVID-19 disease in patients with B-cell lymphopenia.
ABSTRACT
Can higher technological capacity help firms to recover quicker from recessions? Analysing the effects of the Covid-19 pandemic on firm revenues in several countries, we find that firms headquartered in jurisdictions with better digital infrastructure generated relatively higher revenue during the shock period. Improving a country's technological capability by one standard deviation is associated with a relative increase in revenues of the average firm by around 4%. The positive effect of technology is more pronounced among smaller firms, suggesting that it could have helped the recovery of SMEs. © 2021 Elsevier B.V.
ABSTRACT
Background: Venetoclax, a selective bcl-2 inhibitor first approved for CLL has been investigated for the treatment of relapsed myeloma patients, and although it failed to show benefit for myeloma patients as a whole, t(11;14) patients demonstrated exceptional responses in the Bellini trial (Lancet Oncol 2020;21:1630), thus paving the way towards the first genetically targeted treatment in myeloma. Aims: Off label use of venetoclax is on the rise, even though clinicians have to face unanswered questions regarding the right dosage and length of therapy, as well as the potential for adverse events (AEs), especially infections. Real world data could help to elucidate its optimal use, but is very limited as of yet. Methods: We addressed all Hungarian centers treating myeloma to evaluate the efficacy and safety of venetoclax in their practice treating t(11;14) myeloma, collecting data about the treatment duration, AEs, dose modifications and treatment discontinuations, and analyzed response rates as well as progression free and overall survivals (PFS, OS). Results: 50 patients were reported from 7 Hungarian sites. 33 patients were relapsed and heavily pretreated with an average of 4.8 prior lines, whereas 17 patients received venetoclax after a suboptimal initial response to their first line treatment (8 PR, 7 SD, 2 PD) as planned pre-transplantation salvage. Most patients had venetoclax in combination with a proteasome inhibitor and dexamethasone. The response rate was remarkably high given the refractoriness of this cohort: all but two patients responded, with 28% CRs, 38% VGPRs and 30% PRs. The median PFS and OS calculated from initiation of venetoclax dosing were 15.5 and 24 months, respectively, Figure 1. shows the PFS and OS curves of the 2nd line and late line cohorts. The most common AEs were cytopenias, gastrointestinal toxicities and infections, reported in 8, 9 and 10 patients with 1 fatal infection. Two patients had COVID-19 related hospitalization, both recovered. An important point to emphasize is the very high risk nature of this cohort. 13 out of the 47 patients had deletion 17p before venetoclax dosing was initiated, explaining their refractoriness to standard treatments. Notably, of these patients 2 reached CR, 9 VGPR, 1 PR, and only one progressed while on venetoclax treatment. The median PFS and OS were 9.6 and 10 months, respectively. Five patients had plasma cell leukaemia and 1 CNS involvement, the PFS and OS of these ultra-high risk patients were 10 and 12 months. Another important aspect of our analysis was the question of venetoclax dosing, as the appropriate dose in this indication is not yet clear. Reflecting this uncertainty, as well as funding difficulties with this off-label drug, only 2 patients received the 800 mg dose as seen in the Bellini trial;one received 600 mg daily, with all others taking 400 mg or less. To counteract this many centers employed a combination with either clarithromycin or fluconazole, CYP3A inhibitors known to increase venetoclax serum levels two- to threefold. Where available, serum venetoclax levels were monitored to ensure serum levels comparable to regular dosing.Summary/Conclusion: Our results highlight the importance of targeted treatments in multiple myeloma. We experienced lasting responses in quadruple-refractory patients, many with other high risk features. In the newly diagnosed group, where the depth of pre-ASCT response has great impact on PFS, venetoclax may have a role converting suboptimal responses into CRs by eliminating residual disease.
ABSTRACT
Convalescent plasma (CP) with anti-SARS-CoV-2 antibodies tends to be an effective therapeutic approach to aid the treatment of COVID-19 in B-cell depleted patients lacking humoral response to SARS-CoV-2. We here report a series of 20 subjects (13 males and 7 females, at the age of median [range] 56 [27-76] years) with various hematological malignancies and COVID-19 pneumonia. These patients were under anti-CD20 therapy or other chemotherapy and demonstrated a profound B-cell lymphopenia based on flow cytometry analysis of peripheral blood lymphocyte subpopulations. Consequently, they showed undetectable baseline anti-SARS-CoV-2 immunoglobulin (Ig) levels before CP treatment according to Elecsys® SARS-CoV-2 nucleocapsid-and S1-RBD-specific total Ig tests (Roche, Mannheim, Germany). Importantly, 10 patients already received the first dose of CP within 5 days of initiation of antiviral therapy, while the other half were treated with plasma only after 5 days of remdesivir treatment. Although a substantial improvement in clinical symptoms was documented in both subgroups in the presence of improving SARS-CoV-2 Ig levels and decreased inflammatory response monitored via C-reactive protein and ferritin levels as well as oxygen independence, PCR positivity was sustained longer in those subjects who were treated with CP in a delay. CP treatment was well-tolerated, and no adverse event was reported in these cases with resolving pulmonary infiltrations. In conclusion, routinely available serology tests can be utilized to monitor the effect of CP treatment in COVID-19 patients suffering from impaired humoral immunity.