ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for an ongoing global pandemic. Phase III trials have demonstrated excellent efficacies of mRNA vaccines against SARS-CoV-2 in large population studies (Baden LR, NEJM, 2021;Polack FP, NEJM, 2020). Immunosuppressed individuals such as chronic lymphocytic leukemia (CLL) patients are at risk for a suboptimal response to 2 vaccine doses (Herishanu Y, Blood, 2021). The French National Authority for Health recommends the use of a third dose in immunosuppressed patients. However, seroconversion rate after the triple-dose vaccine is not yet known. The objective of our study was to evaluate SARS-CoV-2 antibody responses after the first, second and third doses of the BNT162b2 and mRNA-1273 vaccines. Data were collected from 17 French Innovative Leukemia Organization (FILO) investigating centers and the French CLL patients' association (SILLC). SARS-CoV-2 IgG anti-Spike levels were measured at 4-6 weeks after each vaccine dose. A total of 530 patients and 14 controls were included in the study. Vaccine response was evaluated post-dose 1 for 158 CLL patients, post-dose 2, for 506 patients and post-dose 3 for 66 patients. Peripheral blood lymphocyte subsets were studied post-dose 2 by flow cytometry in 80 CLL patients and 14 controls. The median age of the patients was 71 years (range 37-93), 218 (40%) were treatment-naïve (TN), 136 (26%) had a prior CLL treatment and 176 (34%) were on therapy. Post-dose 1, the global response rate was 27% (43/158). TN patients had a response rate of 34% (23/67), similar to those who had a prior CLL treatment (33%,12/36), and higher compared to on-therapy patients (15%, 8/55, P=0.02). Post-dose 2, the global response rate was 52% (265/506). TN patients had the highest response rate of 72% (151/210) compared to previously treated patients, mostly by immunochemotherapy (60%, 78/130, P=0.02) and on-therapy patients (22%, 36/166, P<0.001) (Figure 1A). Among the 166 on-therapy patients, mostly receiving targeted agents, those receiving venetoclax monotherapy achieved a significantly higher response rate (52%, 12/23) than those treated with BTK inhibitors (BTKi) ibrutinib or acalabrutinib (22%, 23/104, P<0.001). Patients treated with venetoclax+anti-CD20 monoclonal antibodies (n=19) or venetoclax+BTKi (n=6) were all seronegative after the second dose of vaccine (Figure 1B). In multivariate analysis, the variables found to be significantly associated with seroconversion were age >65 years (OR 0.55, 95% CI 0.33-0.92, P=0.02), ongoing CLL treatment (OR 0.13, 95% CI 0.07-0.23, P<0.001) and gamma-globulins ≤6g/L (OR 0.41, 95% CI 0.19-0.88, P=0.03). Flow cytometry results suggest a differential balance of the T CD4+ cell subpopulations in Binet stage A and in patients on targeted therapy compared to healthy controls. Post-dose 2 seronegative patients were proposed a third dose and to date, 66 have been tested for the antibody response 4-6 weeks post-dose 3. The post-dose 3 response rate was 42% (28/66). TN patients and previously treated patients had a significantly higher response rate (57%, 16/28) compared to on-therapy patients (32%, 12/38, P=0.03). We further analyzed patients tested post-dose 2 with the Abbott Architect SARS-CoV-2 IgG anti-Spike assay (n=24). Those who achieved seroconversion after the third dose (n=10) had significantly higher titers post-dose 2 (median 12, IQR 3.0-40.8) compared to those who remained seronegative (n=14) (median 2.2, IQR 0.5-5.1, p<0.01), although both median values are considered below the threshold by the manufacturer. An additional cohort of 40 CLL patients who presented a SARS-CoV-2 infection prior to vaccination participated to the study and was analyzed independently. All patients achieved seroconversion after infection and a single dose of vaccine, even though 30% (n=12) had an ongoing CLL treatment. In conclusion, double-dose mRNA vaccination generated a humoral response in 52% of our CLL cohort and a third dose induced seroconversion in 42% of the patients who remained seronegat ve after the second dose. The major independent predictor of negative antibody response was ongoing treatment with BTKi. The strongest boost to immune response against the virus seems to be SARS CoV-2 infection, as a substantial increase in anti-Spike antibodies was observed in all CLL patients with prior infection, after a single dose vaccination.
ABSTRACT
With the emergence of targeted therapies, defining the best strategy for the treatment of previously untreated CLL patients remains challenging. The aim of this phase 2 study was to compare the efficacy of an association with ibrutinib and venetoclax (IV) to the standard FCR regimen in fit patients with intermediate-risk CLL defined by either unmutated IGHV status, 11q deletion, or complex karyotype in the absence of TP53 abnormality. Patients were randomized 1:1 between two treatment arms, i.e. FCR 6 cycles or IV. After a lead-in phase of ibrutinib as a single agent from the month (M)1 to M3, the total duration of treatment with IV was based on the response achieved at M9;if bone marrow (BM) MRD was <0.01% using flow cytometry, the treatment was continued for 6 additional months until M15 and then stopped;if BM MRD at M9 was ≥0.01%, the treatment with IV was continued for 18 additional months until M27. The primary endpoint was the percentage of patients with BM MRD <0.01% at M27 in both arms. We present here the preliminary results on the first evaluation done at M9 including CT-scan, BM biopsy, and MRD assessment in PB and BM after the inclusion of all the 120 patients as initially planned. One hundred and twenty patients were enrolled from September 2019 to February 2021. The median age was 59 [34-72] and 61 [34-74] years in the FCR and IV arms, respectively. The characteristics of the patients were well-balanced between the 2 arms in terms of gender (male 72% FCR, 74% IV), PS ECOG 0-1 (59% FCR, 68% IV), and Binet stage (A, B, and C 15, 64, 21% for FCR;8.5, 59, and 32% for IV). No major difference in terms of cytogenetic features was noted, all patients but one had unmutated IGHV. At the time of data cut-off for this interim analysis, the median follow-up for all cohort was 12.7 [4.5.9-21.4] months. The frequency of patients presenting all grades adverse events (AE) so far was 90% (grade ≥3: 45%) in the FCR arm and 80% (grade ≥3: 45%) in the IV arm. The rate of infusion-related reactions (IRR) in the FCR arm was 35% on cycle 1-day 1 (14% grade 3-4);for the IV arm, 5% of patients experienced tumor lysis syndrome (TLS) (grade 3 for 1 patient). Ibrutinib doses were reduced for seven patients (four permanently stopped and three resumed at a lower dose because of toxicities (digestive, hepatic, or hematological). Venetoclax was permanently discontinued before M9 in four patients (digestive toxicities and grade 4 neutropenia). Fifty-two serious adverse events were reported of which 22 were in the IV arm (among them one sudden death, one ischemic stroke, one acute coronary syndrome, two atrial fibrillations, two TLS, two acute renal failures, one hepatitis, one neutropenia, two COVID pneumonitis, and one osteoporotic fracture) and 30 in the FCR arm (among them five febrile neutropenia, one hemolytic anemia, one thrombocytopenia, three IRR, three TLS, three COVID pneumonitis, one acute myeloid leukemia, one myelodysplasic syndrome). All patients with COVID pneumonitis had a favorable evolution with the need for intensive care and convalescent plasma for three of them. The first 85 patients included in the study have reached M9 and among them, nine prematurely discontinued the study, (one active hemolysis, one ischemic stroke, one TLS, one hepatitis, and one sudden death in the IV arm;three hematologic toxicities and one early progression in the FCR arm). In the evaluated patients (n=74), 69% of patients in the FCR arm and 43% of patients in the IV arm achieved bone BM MRD <0.01%. The complete (CR, CRi) and partial response rates were 56 and 44% in the FCR arm and 74 and 26% in the IV arm, respectively. In conclusion, preliminary results show a lower BM MRD rate in the IV arm compared to the FCR arm at M9, with toxicity that remains significant and relatively similar between the two arms. However, BM MRD rate may improve after longer exposure to the IV combination and the analysis of the primary endpoint at M27 will be decisive in determining the best therapeutic strategy.
ABSTRACT
With the emergence of targeted therapies, defining the best strategy for the treatment of previously untreated CLL patients remains challenging. The aim of this phase 2 study was to compare the efficacy of an association with ibrutinib and venetoclax (IV) to the standard FCR regimen in fit patients with intermediate risk CLL defined by either unmutated IGHV status, 11q deletion or complex karyotype in the absence of TP53 abnormality. Patients were randomized 1:1 between two treatment arms, ie FCR 6 cycles or IV. After a lead-in phase of ibrutinib as a single agent from month (M)1 to M3, the total duration of treatment with IV was based on the response achieved at M9;if bone marrow (BM) MRD was < 0.01% using flow cytometry, the treatment was continued for 6 additional months until M15 and then stopped;if BM MRD at M9 was ≥ 0.01%, the treatment with IV was continued for 18 additional months until M27. The primary endpoint was the percentage of patients with BM MRD < 0.01% at M27 in both arms. We present here the preliminary results on the first evaluation done at M9 including CT-scan, BM biopsy and MRD assessment in PB and BM after the inclusion of all the 120 patients as initially planned. One hundred and twenty patients were enrolled from September 2019 to February 2021. The median age was 59 [34-72] and 61 [34-74] years in the FCR and IV arms, respectively. The characteristics of the patients were well balanced between the 2 arms in terms of gender (male 72% FCR, 74% IV), PS ECOG 0-1 (59% FCR, 68% IV) and Binet stage (A, B and C 15%, 64%, 21% for FCR;8.5%, 59% and 32% for IV). No major difference in terms of cytogenetic features was noted, all patients but one had unmutated IGHV. At the time of data cut-off for this interim analysis, the median follow-up for the all cohort was 11 [2.9 - 19.8] months. The frequency of all grades adverse events (AE) observed so far was 53% (grade 3-4, 24%) in the FCR arm and 47% (grade 3-4, 17%) in the IV arm. The rate of infusion-related reactions (IRR) in the FCR arm was 35% on cycle 1-day 1 (14% grade 3-4);for the IV arm, 6% of patients experienced tumor lysis syndrome (TLS) (grade 4 for 4 patients). ibrutinib doses were reduced for 7 patients (4 permanently stopped and 3 resumed at a lower dose because of toxicities (digestive, hepatic or haematological)). Venetoclax was permanently discontinued before M9 in 4 patients (digestive toxicities and grade 4 neutropenia). Forty serious adverse events were reported of which 15 in the IV arm (1 sudden death, 1 ischemic stroke, 2 atrial fibrillations, 2 clinical TLS, 1 hepatitis, 1 neutropenia, 4 COVID pneumonitis and one osteoporotic fracture) and 25 in the FCR arm (2 neutropenias, 1 anemia, 1 thrombocytopenia, 1 autoimmune haemolytic anemia, 3 IRR, 4 TLS, 2 COVID pneumonitis, 4 fever episodes of undetermined origin, 1 community-acquired pneumonia, 1 gastrointestinal toxicity, 1 confusion, 2 chest pains, 1 acute myeloid leukemia, 1 myelodysplasic syndrome). The patients with COVID pneumonitis had a favorable evolution with the need for intensive care and convalescent plasma for 3 of them. The first 60 patients included in the study have reached M9 and among them, 6 prematurely discontinued the study, 3 in each arm (active hemolysis, ischemic stroke and sudden death in the IV arm;2 grade 4 hematologic toxicities and 1 early progression in the FCR arm). In the evaluated patients (n=54), 71% of patients in the FCR arm and 48% of patients in the IV arm achieved bone BM MRD < 0.01%. The complete (CR, CRi) and partial response rates were 54% and 46% in the FCR arm and 76% and 24% in the IV arm respectively. In conclusion, the preliminary results show a lower BM MRD rate in the IV arm compared to the FCR arm at M9, with a toxicity that remains significant and relatively similar between the two arms. However, BM MRD rate should improve after longer exposure to the IV combination and the analysis of the primary endpoint at M27 will be decisive in determining the best therapeutic strategy. Disclosures: Quinquenel: Abbvie: Honoraria;Jansse : Honoraria;AstraZeneca: Honoraria. Laribi: Le Mans Hospital: Research Funding;Novartis: Other: Personal Fees, Research Funding;Takeda: Other: Personal Fees, Research Funding;BeiGene: Other: Personal Fees;IQONE: Other: Personal Fees;AbbVie: Other: Personal Fees, Research Funding;Astellas Phama, Inc.: Other: Personal Fees;AstraZeneca: Other: Personal Fees;Jansen: Research Funding. Cymbalista: Lilly-LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;ASTRA ZENECA: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leblond: AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Lilly: Consultancy;AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support;Roche: Honoraria;Amgen: Honoraria;Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress;Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress;Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Ferrant: Janssen: Other: Travel, Accommodations, Expenses;AbbVie: Honoraria, Other: Travel, Accommodations, Expenses;AstraZeneca: Honoraria. de Guibert: Janssen: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria;Gilead: Consultancy, Honoraria. Feugier: Astrazeneca: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;Abbvie: Consultancy, Honoraria;Amgen: Honoraria;Janssen: Consultancy, Honoraria. Cartron: Roche, Celgene-BMS: Consultancy;Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding.