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.
ABSTRACT
On behalf of the GRAALL group, the Czech Republic ALL group, the Finland ALL group and the EWALL group. Introduction. Treatment of older patients (pts) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains an unmet medical need. Inotuzumab ozogamicin (INO), an anti-CD22 antibody conjugated to calicheamicin, is approved for the treatment of relapsed/refractory BCP-ALL in adults, sinusoidal obstruction syndrome (SOS) being the major adverse event associated with INO. A previous first line study conducted by the MDACC in pts 60 years or older successfully used INO in combination with a lower intensity version of the hyper-CVAD (mini-hyper-CVD). Due to the occurrence of SOS, the total doses were fixed at 1.3 mg/m² for cycle 1 followed by 3 cycles at 1 mg/m² (Kantarjian H et al. Lancet Oncol, 2018). Here, we aimed to assess the activity and safety of fractionated INO at a reduced dosage in combination with low-intensity chemotherapy as frontline therapy for older pts with CD22+ Philadelphia chromosome-negative (Ph-neg) BCP-ALL. Methods. EWALL-INO is a single arm prospective phase 2 multicentric study conducted in European centers belonging to the EWALL group. Eligibility criteria were pts aged 55y or older, performance status ≤2, and newly diagnosed CD22+ (20% or more of positive blast cells) Ph-neg BCP-ALL without central nervous system involvement. After a prephase including 5 days (D) of dexamethasone (DEX) 10mg per D and a single intrathecal injection (IT), the induction regimen was begun and split in 2 parts. Induction part I (Induc1) consisted of one triple IT, vincristine (VCR) 2 mg (1 mg over 70y) D1 D8 D15 D22 and DEX 20 mg D1D2 D8D9 D15D16 D22D23 combined with 3 injections of INO (0.8 mg/m² D1, 0.5 mg/m² D8 and D15). Induction part II (Induc2) was offered to pts in CR or CRp (CR with platelets < 100 G/l) after Induc1 or as salvage therapy. Induc2 consisted of DEX 20mg D1D8, cyclophosphamide (CY) 300 mg/m² D1 to D3, one triple IT D2 and 2 injections of INO (0.5 mg/m² D1 and D8). Pts in CR/CRp were programmed to receive 6 blocks of consolidation (Ara-C 1.5g/m²/12h adapted to renal clearance D1D2 and DEX 10mg/12h D1D2, cycles 1 and 4;Methotrexate (MTX) 1.5 g/m² over 24h D1, VCR 1 or 2 mg D1, one triple IT D2 and 6-mercaptopurin (6-MP) D1 to D7, cycles 2 and 5;CY 500 mg/m² D1D2, VP16 75 mg/m² D1D2, one triple IT D2 and MTX 25 mg/m² D1, cycles 3 and 6) followed by a POMP maintenance (VCR, 6-MP, MTX, DEX) during 18 months. Allograft was allowed after at least 3 blocks of consolidation at the discretion of the investigators. The evaluable population was pts who received at least 1 dose of INO. Analyses were by modified intention to treat and performed JUN 28, 2021. All pts gave informed consent. The study is registered at ClinicalTrials.gov under the NCT number: NCT03249870. Results. Between DEC 29, 2017 and JUN 22, 2021, 115 pts (out of 130 planned pts) were enrolled including 6 pts with screen failure. The first 90 eligible pts (up to MAR 1, 2021) were considered for this analysis to obtain a minimum of 4 months follow-up. Median age was 69y (range 55-84) and median follow-up for alive pts was 1.18 years (range 0.3-3.5). At time of analysis, 90 and 88 pts had started induc1 and induc2, respectively. Treatment related mortality was 2.2% (2/90) and CR/CRp rate was 85.5% (77/90, 6 CRp) after induc1. Three cases relapsed between induc1 and induc2 and 5 pts were salvaged by induc2 allowing to a CR/CRp rate of 87.7% (79/90, 8 CRp) after induc2. One pts died from refractory disease during induc2. One, 2, 3 4 and 5 injections of INO were administered to 2 (2.2%), 2(2.2%), 11 (12.2%), 2 (2.2%) and 73 pts (81.1%) respectively. Only 6 pts were allografted. One-year OS was estimated to be 78.5% (95%CI 68-85.9) and median OS was not reached. One-year relapse free survival was 74.5% (95CI 63.5-82.6) (Figure 1). Grade 3-4 liver toxicity was observed in 8 pts (8.8%) during the study including 3 pts (3.3%) developing SOS, 2 related to INO during induc1 and one occurred after transplant. Twenty-nine pts died during the follow-up, 16 from relapses (overall incidence 18%) and 13 from adverse events (overall incidence 14.4%), including one COVID19 fatal infection during consolidation. Conclusion. Fractionated inotuzumab ozogamicin at reduced doses (0.8/0.5/0.5/0.5 mg/m²) combined with low-intensity chemotherapy is a very active and well tolerated frontline therapy for older patients with CD22+ Ph-neg BCP-ALL. [Formula presented] Disclosures: Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Huguet: Novartis: Other: Advisor;Jazz Pharmaceuticals: Other: Advisor;Celgene: Other: Advisor;BMS: Other: Advisor;Amgen: Other: Advisor;Pfizer: Other: Advisor. Raffoux: ABBVIE: Consultancy;PFIZER: Consultancy;CELGENE/BMS: Consultancy;ASTELLAS: Consultancy. Boissel: CELGENE: Honoraria;Servier: Consultancy, Honoraria;Incyte: Honoraria;Amgen: Consultancy, Honoraria, Research Funding;Novartis: Consultancy, Honoraria, Research Funding;Bristol-Myers Squibb: Honoraria, Research Funding;PFIZER: Consultancy, Honoraria;JAZZ Pharma: Honoraria, Research Funding;SANOFI: Honoraria. Dombret: Amgen: Honoraria, Research Funding;Incyte: Honoraria, Research Funding;Jazz Pharmaceuticals: Honoraria, Research Funding;Novartis: Research Funding;Pfizer: Honoraria, Research Funding;Servier: Research Funding;Abbvie: Honoraria;BMS-Celgene: Honoraria;Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Inotuzumab ozogamicin as first line therapy in newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia