Fractionated Inotuzumab Ozogamicin Combined with Low-Intensity Chemotherapy Provides Very Good Outcome in Older Patients with Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia: First Results from the EWALL-INO Study

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

Antibody Response to 2-Dose Sars-Cov-2 mRNA Vaccine in Allogeneic Hematopoietic Cell Transplant Recipients

INTRODUCTION Immunocompromised patients have been excluded from initial trials evaluating SARS-CoV-2 mRNA vaccines and there is a critical need to warrant vaccine efficacy in hematopoietic stem cell transplant (HSCT) recipients. In this study, we evaluated antibody responses to 2 doses mRNA SARS-CoV-2 vaccine in allogeneic HSCT recipients. METHODS We retrospectively enrolled successive hematopoietic cell transplant recipients across France who completed the 2-dose SARS-CoV-2 mRNA vaccine (BNT162b2 or mRNA-1273) between January 1 st and July 15 th 2021. All included patients had an available semi-quantitative antispike serologic testing after the second dose (from Roche, DiaSorin, Abbott or Siemens). We excluded patients with a prior COVID-19 confirmed by serology or PCR. For detectable antibody, we calculated the binding antibody units per milliliter (BAU/mL) according to the WHO International Standard by applying conversion factors given by the manufacturers (Kristiansen et al., The Lancet 2021). Antibody response was categorized as “weak” or “good” with a threshold of 264 BAU/mL which has been associated to an estimate of 80% of mRNA vaccine-induced protection against symptomatic COVID-19 in immunocompetent patients (Feng S. et al., medRxiv 2021). We built a multivariate logistic regression model to assess factors independently associated with the absence of antibody response after the second dose of mRNA vaccination. RESULTS Overall, 620 allogeneic HSCT recipients from 12 hospitals across France were included in the analysis (60% male with a median age of 59 years old [IQR 47-66]), most with a myeloid (69%) or lymphoid (26%) malignancies. Donors were matched unrelated for 51%, HLA-identical sibling for 31% and haplo-identical for 18%. Thirty-one percent of HSCT recipients underwent a myeloablative conditioning, while 69% received a reduced intensity conditioning. The two doses of vaccines were given one month apart and the median time between transplantation and the initiation of vaccination was 29 months [IQR 14-58]. At a median of 33 [IQR 27-50] days after dose 2, an antibody response was detectable in 496 patients (80% [95CI: 77 to 83%]). Median [IQR] antibody levels was 243 BAU/mL [29.4-1391]. We classified detectable antibody responses as “weak” in 189 patients (30% [95CI 27 to 34%]) and as “good” in 306 (49% [95CI: 45 to 53%]). In the multivariate analysis including 533 patients (420 with detectable antibodies), factors associated with the absence of humoral responses were a time-interval from HSCT < 12 months (ajusted Odds-Ratio (aOR) 2.8 [95CI 1.6 to 4.8]), absolute lymphocyte count <1G/L (aOR 3.0 [95CI 1.7 to 5.0]), systemic immunosuppressive treatments within 3 months of vaccination (aOR 4.5 [95CI 2.7 to 7.5]), together with the use of rituximab within 6 months (aOR 15.1 [95CI 4.3 to 52.7]). In a subsequent multivariate analysis conducted a subset of 227 patients (170 with detectable antibodies) with available gammaglobulinemia as well as B and T lymphocytes counts, factors remaining associated with the absence of antibody response were only low B-lymphocytes count (aOR 5.5 [95CI 2.4 to 12.3]) and time-interval from HSCT < 12 months (aOR 3.3 [95CI 1.5 to 7.2]). CONCLUSION After 2 dose mRNA vaccination, the majority of allogeneic HSCT recipients developed an antibody response although a significant proportion of these responses may be insufficient. Studies are still needed to investigate the effect of a third vaccine dose in patients with a null or weak humoral response. Disclosures: Loschi: Servier: Ended employment in the past 24 months, Honoraria;Novartis: Ended employment in the past 24 months, Honoraria;Gilead: Ended employment in the past 24 months, Honoraria;AbbVie: Ended employment in the past 24 months, Honoraria;CELGENE/BMS: Honoraria;MSD: Honoraria.