ABSTRACT
Donor specific antibodies (DSA) are known to be associated with increased mortality following heart transplant (HT). Despite the high overall burden of disease from novel coronavirus (COVID-19) among HT recipients, little is known about the subsequent development of de novo or increased DSA (diDSA) in COVID-19 survivors. We performed a retrospective analysis at 8 large centers of HT recipients diagnosed with COVID-19 between 3/1/2020 and 3/31/2021. Acting on anecdotal reports, we began checking DSA approximately 3, 6, and 12 months after acute COVID-19 as standard of care. Incidence of diDSA, defined as an increase in MFI by >2500, was determined. Treatment of acute cellular rejection (ACR) and antibody mediated rejection was recorded. Of 380 HT patients who developed COVID-19, 191 (70% male) had DSA data available by study end-date. A total of 5% developed diDSA by 3 months (11/191), 10% by 6 months (17/172) and 18% by 12 months (24/131). The median time for development of diDSA was 144 days. Patients with pre-existing DSA had a significantly increased incidence of diDSA compared to those without pre-existing DSA (15/32 vs 9/159, p<0.001). There was no difference in diDSA between patients who had immunosuppression reduced during acute COVID-19 and those who did not (6/47 vs 17/107, p=0.890). Compared to those without diDSA, there was a significant increase in the incidence of ACR (ISHLT grade ≥2R) in the year following infection in those with diDSA (3/165 vs 4/24, p=0.006). This study demonstrates a high incidence of diDSA (18%) at 12 months among HT recipients after COVID-19. In addition, diDSA was more common among those with pre-existing DSA, and diDSA was associated with higher incidence of ACR. [ABSTRACT FROM AUTHOR] Copyright of Journal of Heart & Lung Transplantation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
ABSTRACT
Background: Maintenance in FL patients (pts) improves progression free survival (PFS). SARS-Cov2 pandemic posed unique challenges for immunocompromised pts. Aims: The aim is to evaluate the outcome of FL pts in maintenance with antiCD20-MoAb during SARS-Cov2 pandemic and how suspension of therapy affected lymphoma outcome and the risk of SARS-Cov2 infection and its morbidity and mortality. Methods: This is an observational, multicenter, retrospective and prospective study. Results: A total of 420 from 18 Italian Hematological Centers were included in the analysis. Median age was 62 years old (range 27-91 years), 216 pts (51%) were male. Main clinical characteristics of the population were: histological grade 1-2 vs 3A in 288 (69%) vs 109 (26%), while not valuable in 23 (5%) pts;limited I-II vs advanced III-IV stage in 57 (14%) vs 361 (86%) pts, not reported in 2 cases. FLIPI score was low vs intermediate vs high in 71 (17%) vs 151 (36%) vs 192 (46%) patients, respectively, not valuable in 6 cases. All 420 patients included were in maintenance treatment with antiCD20 MoAb at the time of the onset of SARS-Cov2 pandemic (March 2020): 333 (79%) pts were receiving maintenance after a first line, while 87 (21%) after a second line. 342 (81%) pts were receiving Rituximab, while 75 (18%) Obinutuzumab, 3 patients did not start the planned maintenance because of pandemic spread. Status of disease after induction was complete remission (CR) in 374 (89%), partial response (PR) in 41 (10%), progressive disease (PD) in 1, not evaluated in 4 pts, respectively. At the end of maintenance was CR in 265 (63%), PR in 19 (4%), stable disease (SD) in one and PD in 14 (3%) patients, respectively, maintenance is stiil ongoing in 121 (29%) pts. Because of SARS-Cov2 pandemic from March 2020 consequences on maintenance treatment were: temporary suspension in 122 (29%), definitively interruption in123 (29%), no modification in 175 (42%) of pts, respectively. Median number of maintenance treatment administered at the time of SARS-Cov2 pandemic onset was 2 (range 1-12), median number of courses administered at the time of analysis was 8 (range 0-12), in patients who modified treatment because of pandemic median number of performed courses was 7 (range 0-11) and median number of lost cycles were 2 (range 1-12). Pts were divided into two groups according to type of approach to maintenance during pandemic: pts who interrupted maintenance (temporary or definitively): groups A (245 (58%) pts) vs pts who did not modified maintenance: group B (175 (42%) pts). No differences in clinical characteristics, type of therapy and response were observed between the two groups. 29(7%) relapses were observed: 16 (7%) vs 13 (7%) in group A vs B, respectively. 70 (17%) pts experienced SARS-Cov2 positivity: 47 (19%) vs 23 (13%) in group A vs B, respectively. 53 (76%) pts had symptomatic COVID syndrome and 43 (61%) were hospitalized, with no differences between the two groups. Anti-SARS-Cov2 vaccine was administered in 349 patients, serology assessment was done in 46% of cases, showing 21 (13%) reactive vs 138 (87%) not reactive pts, with no differences between the two groups. 21 (30%) pts died because of COVID: 9 (19%) vs 12 (52%) in groups A vs B, respectively. Summary/Conclusion: Suspension of maintenance treatment during SARS-Cov2 pandemic did not show a protection in terms of SARS-Cov2 positivity and morbidity. A trend in lower mortality is suggested. No differences in terms of relapse rate were observed, but longer follow up is needed.
ABSTRACT
Background: Maintenance in FL patients (pts) improves progression free survival (PFS). SARS-Cov2 pandemic posed unique challenges for immunocompromised pts. Methods: This is an observational, multicenter, retrospective and prospective study. The aim is to evaluate the outcome of FL pts in maintenance with antiCD20-MoAb during SARS-Cov2 pandemic and how suspension of therapy affected lymphoma outcome and the risk of SARS-Cov2 infection and its morbidity and mortality. Results: 420 pts from 18 Italian Centers were included. Median age was 62 years old (range 27-91), 216 pts (51%) were male. Main clinical characteristics were: histological grade 1-2 vs 3A vs not valuable in 288 (69%) vs 109 (26%) vs 23 (5%), respectively;advanced stage in 361 (86%), high FLIPI score in 192 (46%) pts. All 420 pts were in antiCD20-MoAb maintenance at the time of SARS-Cov2 pandemic onset (March 2020): 333 (79%) were receiving maintenance after a first line, while 87 (21%) after a second line. 342 (81%) pts were receiving Rituximab, while 75 (18%) Obinutuzumab, 3 pts did not start the planned maintenance. Status of disease after induction was complete remission (CR) in 374 (89%), partial response (PR) in 41 (10%), progressive disease (PD) in 1, not evaluated in 4 patients, respectively. At the end of maintenance was CR in 265 (63%), PR in 19 (4%), stable disease (SD) in one and PD in 14 (3%) pts, maintenance is ongoing in 121 (29%) pts. Because of SARS-Cov2 pandemic maintenance treatment was temporary suspended in 122 (29%), definitively interrupted in123 (29%), not changed in 175 (42%). Median number of maintenance treatment administered at March 2020 was 2 (range 1-12), in pts who modified treatment median number of performed vs lost courses was 7 (range 0-11) vs 2 (range 1-12). Patients were divided into two groups according to the approach to maintenance during pandemic: pts who interrupted maintenance (temporary or definitively): groups A (245 (58%) cases) vs pts who did not modified maintenance: group B (175 (42%)). No differences in clinical characteristics, type of therapy and response were observed between the two groups. 29(7%) relapses were observed: 16 (7%) vs 13 (7%) in group A vs B. 70 (17%) pts experienced SARS-Cov2 positivity: 47 (19%) vs 23 (13%) in group A vs B. 53 (76%) pts had symptomatic COVID and 43 (61%) were hospitalized, with no differences between the two groups. Anti-SARS-Cov2 vaccine was administered in 349 patients, serology assessment was done in 46% of cases, showing 21 (13%) reactive vs 138 (87%) not reactive patients, with no differences between the two groups. 21 (30%) pts died because of COVID: 9 (19%) vs 12 (52%) in groups A vs B. Conclusions: Suspension of maintenance during SARS-Cov2 pandemic did not show a protection in terms of SARS-Cov2 positivity and morbidity. A trend in lower mortality is suggested. No differences in terms of relapse rate were observed, but longer follow up is needed.
ABSTRACT
This paper tackles the problem of predicting the protein-protein interactions that arise in all living systems. Inference of protein-protein interactions is of paramount importance for understanding fundamental biological phenomena, including cross-species protein-protein interactions, such as those causing the 2020-21 pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Furthermore, it is relevant also for applications such as drug repurposing, where a known authorized drug is applied to novel diseases. On the other hand, a large fraction of existing protein interactions are not known, and their experimental measurement is resource consuming. To this purpose, we adopt a Graph Signal Processing based approach modeling the protein-protein interaction (PPI) network (a.k.a. the interactome) as a graph and some connectivity related node features as a signal on the graph. We then leverage the signal on graph features to infer links between graph nodes, corresponding to interactions between proteins. Specifically, we develop a Markovian model of the signal on graph that enables the representation of connectivity properties of the nodes, and exploit it to derive an algorithm to infer the graph edges. Performance assessment by several metrics recognized in the literature proves that the proposed approach, named GRAph signal processing Based PPI prediction (GRABP), effectively captures underlying biologically grounded properties of the PPI network. Author
ABSTRACT
Background: Undetectable MRD (uMRD) has become an achievable endpoint for patients (pts) with CLL, in particular using the BCL2 inhibitor VEN allowing treatment discontinuation in a MRD-driven approach. uMRD can be reached in a proportion of pts with VEN mono, and in larger fraction in combination with the BTK inhibitor IBR. It remains to be established who can achieve best responses with single agent or combination strategies. Aims: This phase 2 multicenter MRD-driven Italian study aims at discontinuing treatment upon reaching uMRD in pts with relapsed/refractory CLL treated with VEN mono or through the addition of IBR in pts who did not achieve uMRD with the single agent. Methods: VEN mono (up to 400 mg/day as per label) was administered for 12 months. MRD in peripheral blood (PB) and bone marrow (BM) was evaluated using the ERIC 6-color flow panel. Pts with uMRD in both PB and BM at C12D1 discontinued VEN at C12D28. Pts with detectable MRD in PB and/or BM added IBR 420 mg/day from C13D1 and continued both drugs up to C24D28, uMRD, progression or toxicity (whichever first). After C24D28, pts with detectable MRD and still in response continued IBR alone. The primary endpoint was uMRD4 (<1 CLL cell in 104 leukocytes) in both PB and BM. Results: 38 pts (recruited from Nov 2017 to Jul 2018) started VEN. Median number of prior therapies was 1 (range 1-4), 61% were previously treated with FC+/-R;8/33 (24%) carried del(17p);10/30 (33%) TP53 mutations, and 24/30 (80%) unmutated IGHV. One pt discontinued treatment due to myelodysplasia (unrelated to VEN) and 1 pt due to COVID-19. As of 31 Jan 2021, overall response rate with VEN mono was 36/38 (95%), 19 CR and 17 PR. As per protocol, 17 pts (45%) with uMRD4 in PB and BM at C12D1 discontinued VEN at C12D28. 19 (55%) responsive cases with detectable MRD at C12D1 added IBR to VEN from C13D1. By combining IBR and VEN for a median of 7 months (range 3-10) 5/10 pts in PR improved their response to CR, 16/19 (84%) achieved uMRD4 in both PB and BM (Fig. 1), thus stopping both therapies. The remaining 3/19 continued IBR. After a median follow up of 30 months, median PFS has not been yet reached;3 pts progressed without treatment need, 1 pt restarted VEN mono as per protocol, 2 pts developed Richter transformation. 11/33 pts (33%) who discontinued treatment in uMRD, after a median observation of 30 months remain uMRD (6 treated with VEN only). No cases of clinical and/or laboratory tumor lysis syndrome were reported in 39 pts (1 excluded from the efficacy analysis because of atypical phenotype). Adverse events were mild, with no discontinuations or dose reductions;with prolonged follow-up no new relevant toxicities occurred. Summary/Conclusion: Our updated results demonstrated that a sequential MRD-guided approach is feasible and leads to an overall uMRD in 33/38 pts (87%) with either VEN mono or in combination with IBR. Interestingly, 84% of pts who did not achieve uMRD after VEN alone obtained uMRD after the addition of IBR and the remaining 3 patients who did not obtain uMRD even after the combination, could be selected for continuous IBR. Median PFS is not yet reached after 30 months of follow-up. This MRD-driven sequential approach allows to reach identical depth of response in each patient enrolled in the study using a personalized intensification avoiding unnecessary drug exposure, ultimately identifying the few pts that may benefit from continuous IBR. Time to clinical progression, response to VEN retreatment, and characteristics of pts with persistent MRD remain to be established.
ABSTRACT
The treatment of chronic lymphocytic leukemia (CLL) has been radically changed in the last years thanks to the targeted therapies, including kinase (i.e. ibrutinib) and BCL2 (i.e. venetoclax) inhibitors. Venetoclax (VEN) in particular is able to obtain undetectable minimal residual disease (uMRD), though only in a proportion of patients (pts) when given as single agent, thus warranting the need of different strategies in those not achieving uMRD. We designed a phase 2 multicenter Italian study where ibrutinib (IBR) is added to VEN based on a MRD-driven strategy aiming at obtaining uMRD and discontinuing both treatments in pts who did not achieve uMRD with VEN mono. Study treatment started with VEN (ramp up to 400 mg/day as per current label) for 12 months. MRD status in peripheral blood (PB) and bone marrow (BM) was evaluated using the 6-color flow cytometry assay recommended by ERIC (CD5/CD81/CD79b/CD19/CD43/CD20). Pts with uMRD in both PB and BM at C12D1 discontinued VEN at C12D28 and entered the follow-up phase. Pts with detectable MRD in PB and/or BM added IBR 420 mg/day starting from C13D1 and continued both drugs up to maximum C24D28, uMRD, progression or unacceptable toxicity (whichever occurs first). After C24D28, pts with detectable MRD and still in response continued IBR alone. The primary endpoint was uMRD4 (<1 CLL cell in 104 leukocytes) in both PB and BM. We report here the results as of 15Jul2020 (data cutoff). Thirty-eight pts (recruited from Nov 2017 to Jul 2018) fulfilled eligibility and started VEN. Baseline characteristics included: median number of prior therapies 1 (range 1-4) (60.6% previously treated with FCR or FC);del(17p) in 8/33 (24%);TP53 mutations in 10/30 (33%), and unmutated IGHV in 24/30 (80%). At the data cut-off, 35/38 evaluable pts still in the study have reached C24D1, 1 pt discontinued treatment due to myelodisplasia (considered unrelated to study treatment) before C12D1 and 1 pt progressed on VEN monotherapy shortly before that timepoint, 1 evaluation is still missing due to COVID-19 restrictions. At C12D1, uMRD4 in PB was achieved in 19/38 (50%) pts (Figure 1), 17/19 (89.5%) had uMRD4 confirmed in BM. Overall response rate with VEN single-agent was 36/38 (94.7%), 9 CR and 27 PR. As per protocol, the 17 pts (45%) with uMRD4 in PB and BM at C12D1 discontinued VEN at C12D28. Nineteen responsive cases with detectable MRD at C12D1 added IBR to VEN starting from C13D1. The combination of IBR and VEN led to an improved reduction of the depth of MRD in all but 3 pts with 16/19 (84%) achieving uMRD4 in both PB and BM between C16D1 (first MRD assessment after starting IBR) and C24D1, thus stopping both therapies as per protocol. After a median follow-up of 25.4 months (range 6.1-33.5) from treatment initiation, no clinical progression was observed among those discontinuing treatment in uMRD, while MRD4 relapse occurred in 21/33. Median time to MRD4 relapse in those who achieved uMRD at any timepoint and discontinued treatment was 4 months (range 2-13). Twelve pts (6 treated with VEN only) remain uMRD after stopping treatment, with a median observation of 13 months (range 3+-18+) since confirmed uMRD4. Safety data were analyzed in the intention-to-treat cohort (39 pts). No cases of clinical tumor lysis syndrome (TLS) and/or biochemical TLS were reported in the 39 pts exposed to VEN. Adverse events (AEs) were mild, with no treatment discontinuations or dose reductions. Five Serious AEs (Table 1) and 130 AEs (Table 2) occurred in 28 patients, without any SUSARs. All 5 SAEs were deemed unrelated to study drug(s) and 4/5 have resolved without sequelae. In conclusion, we here present the updated results of our study including the combination phase of VEN with IBR. This sequential MRD-guided approach was feasible and led to deeper responses in about 85% of pts not achieving uMRD4 after VEN alone. With this tailored and time-limited strategy 33 out of 38 pts (87%) obtained uMRD4 in PB and BM either after VEN monotherapy or the IBR-VEN combination, indicating we may reach identical depth of re ponse with a personalized intensification and avoid unnecessary drug exposure. Time to clinical progression and response to VEN retreatment in this cohort remain to be established as well as the biological characteristics of those pts with persistent MRD despite the combined treatment. Updated results with further sequential MRD and clinical monitoring after treatment discontinuation will be presented at the meeting. [Formula presented] Disclosures: Scarfo: Gilead: Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Honoraria;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Farina: Abbvie: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees. Gaidano: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astrazeneca: Membership on an entity's Board of Directors or advisory committees;Sunesys: Membership on an entity's Board of Directors or advisory committees. Reda: Janssen: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees. Coscia: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees;Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Karyopharm Therapeutics: Research Funding. Laurenti: Roche: Honoraria;Gilead: Honoraria;Janssen: Honoraria;AbbVie: Honoraria. Varettoni: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees;AbbVie: Other: Travel/accommodations/expenses;Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses. Ghia: Lilly: Consultancy, Honoraria;Sunesis: Consultancy, Honoraria, Research Funding;Adaptive, Dynamo: Consultancy, Honoraria;MEI: Consultancy, Honoraria;Celgene/Juno: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding;BeiGene: Consultancy, Honoraria;Acerta/AstraZeneca: Consultancy, Honoraria;ArQule: Consultancy, Honoraria;Gilead: Consultancy, Honoraria, Research Funding;AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding;Novartis: Research Funding.