ABSTRACT
Not available.
ABSTRACT
The coronavirus disease of 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in increased morbidity and mortality in patients with impaired immunity, hematologic malignancies, and immunosuppressive regimens. COVID-19 can cause a cytokine storm with some patients benefiting from blockade of the pro-inflammatory cytokine, interleukin 6 (IL6). As Castleman disease (CD) is an atypical lymphoproliferative disorder that can involve a cytokine storm and often requires immunosuppressive therapies, including IL6 inhibition, we sought to evaluate outcomes following COVID-19 and SARS-CoV-2 vaccination in CD patients. We administered a survey in April 2021 to characterize experiences with COVID-19 and SARS-CoV-2 vaccination among 300 CD patients enrolled in ACCELERATE, a natural history registry of CD patients. Among 128 respondents, the prevalence of SARS-CoV-2 infection (16/95, 17%), severe disease (1/16, 6%), vaccination rates (112/128, 88%), and vaccine adverse effects after dose one (62/112, 55%) were comparable to the general U.S. population. While there were two cases of CD flares occurring shortly after SARS-CoV-2 infection (N=1) and vaccination (N=1), over 100 patients in this study that were infected and/or vaccinated did not experience CD flares. The median anti-spike titer six months after the second dose among CD patients was comparable to individuals with other immune-related diseases and healthy populations. Data from this small cohort suggest that, despite being on immunosuppressive therapies, CD patients do not appear to be at increased risk of poor COVID-19 outcomes and can mount a humoral response to SARS-CoV-2 vaccination. This study was registered on clinicaltrials.gov (#NCT02817997).
ABSTRACT
ABSTRACT: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard-of-care for patients with advanced-stage diffuse large B-cell lymphoma (DLBCL), despite findings that patients with nongerminal center B-cell like (non-GCB) have significantly worse outcome with this regimen. We evaluated the prognostic significance of baseline risk factors, including cell of origin (COO) classified by the Hans algorithm, within an alternative chemoimmunotherapy program. At Memorial Sloan Kettering Cancer Center (MSK), 151 patients with DLBCL received sequential R-CHOP induction and (R)-ICE (rituximab, ifosfamide, carboplatin, and etoposide) consolidation. Outcome analysis based on COO was validated with a propensity score-matched cohort treated with R-CHOP from the Mayo Clinic component of the Molecular Epidemiology Resource (MER). Among the patients with GCB (n = 69) and non-GCB (n = 69) at MSK, event-free survival (EFS) of non-GCB was superior to that of GCB (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.29-0.98). Overall survival (OS) demonstrated an association in the same direction but was not statistically significant (HR, 0.68; 95% CI, 0.33-1.42). Propensity score-matched patients from MSK (n = 108) demonstrated a small attenuation in the HRs for EFS (HR, 0.57; 95% CI, 0.27-1.18) and OS (HR, 0.76; 95% CI, 0.33-1.79) and were no longer statistically significant. In contrast, the matched MER cohort (n = 108) demonstrated an EFS association (HR, 1.17; 95% CI, 0.70-1.95) and OS association (HR, 1.13; 95% CI, 0.64-2.00) in the opposite direction, but were also not statistically significant. R-CHOP induction and (R)-ICE consolidation may overcome the negative prognostic impact of the non-GCB phenotype, per the Hans algorithm, and can be preferentially selected for this population. This trial was registered at www.ClinicalTrials.gov as #NCT00039195 and #NCT00712582.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Cyclophosphamide , Doxorubicin , Ifosfamide , Lymphoma, Large B-Cell, Diffuse , Prednisone , Rituximab , Vincristine , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/therapeutic use , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Etoposide/therapeutic use , Ifosfamide/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/mortality , Prednisone/therapeutic use , Prognosis , Rituximab/therapeutic use , Treatment Outcome , Vincristine/therapeutic use , Case-Control StudiesABSTRACT
PI3K-δ inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities, leading to market withdrawals. We previously demonstrated activity of the PI3K-δγ inhibitor duvelisib in T cell lymphomas (TCLs) that was associated with inflammatory adverse events. As reported here, we conducted a phase 1b/2a study of duvelisib in combination with either romidepsin (n = 66) or bortezomib (n = 32) in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the safety and maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. The most common adverse events were neutropenia (42%, 25/59) and fatigue (37%, 22/59) in patients treated with duvelisib and romidepsin and diarrhea (48%, 11/23) and neutropenia (30%, 7/23) in patients treated with duvelisib and bortezomib. Duvelisib and romidepsin resulted in less grade 3/4 hepatotoxicity (14%, 8/59) compared to 40% (14/35) in our previous study with duvelisib monotherapy. This was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. Secondary endpoints of overall and complete response rates were 55% (35/64) and 34% (22/64) for patients treated with duvelisib and romidepsin and 34% (11/32) and 13% (4/32) for patients treated with duvelisib and bortezomib. Among patients with peripheral T cell lymphomas (PTCLs), overall and complete response rates of duvelisib and romidepsin were 56% (27/48) and 44% (21/48), respectively, with exploratory analyses showing increased response rates in patients with a follicular helper T cell subtype. These findings support further development of combined PI3K and histone deacetylase (HDAC) inhibition in TCLs and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations. ClinicalTrials.gov identifier: NCT02783625 .