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 conju...
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| Veröffentlicht in: | Blood 2021-11, Vol.138 (Supplement 1), p.511-511 |
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| creator | Chevallier, Patrice Leguay, Thibault Doubek, Michael Huguet, Francoise Salek, Cyril Cabannes, Aurélie Wartiovaara-Kautto, Ulla Saillard, Colombe Raffoux, Emmanuel Cluzeau, Thomas Leprêtre, Stéphane Balsat, Marie Berceanu, Anna Boissel, Nicolas Clappier, Emmanuelle Morisset, Laure Gardin, Claude Dombret, Hervé Rousselot, Philippe |
| description | 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 all |
| doi_str_mv | 10.1182/blood-2021-148625 |
| format | Article |
| fullrecord | <record><control><sourceid>elsevier_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1182_blood_2021_148625</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0006497121025040</els_id><sourcerecordid>S0006497121025040</sourcerecordid><originalsourceid>FETCH-LOGICAL-c1425-1e70a7885d5ed80c2f71cf4a3b0aaaa102840aa92ee05e4d4e7a9bcb1344cd1a3</originalsourceid><addsrcrecordid>eNp9kU-P0zAQxQMCie7CB-A2d-TFdp1NCqeS3S6Voqbi7zFy7EljSOLKdlplPz1eypm5eCTr_d7TvCR5y-gNYzl_3_TWasIpZ4SJ_Janz5MFS3lOKOX0RbKglN4SscrYq-TK-1-UMrHk6eLZ1cZJFYwdZUAN29GG6XEaZAPVoz3IwSgzQmGHxozx-2xCB6U9k-0YcPQmzFB0ONjQoZPHGfbOnoxGDz_QzfAQE0E1BWUHhIipeo0O9jIYHIO_wHZ47me4M_IwWh8dijvO38G-M73U2B87I6ODs4P1EUJ2eIjqE8InUmDfRz9Uk_PWwVpNAaGch2Nnm176YBSUOP3GwcgPsDHOB_iCfuqjcRt5ECPD_c91WZLtroKvYdLz6-RlK3uPb_6918n3zf234jMpq4dtsS6JYoKnhGFGZZbnqU5R51TxNmOqFXLZUBmHUZ6LuK04Ik1RaIGZXDWqYUshlGZyeZ2wC1c5673Dtj46M0g314zWT2XWf8usn8qsL2VGzceLBmOwk0FXexXPqFCbeINQa2v-o_4DYg6tQg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>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</title><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Chevallier, Patrice ; Leguay, Thibault ; Doubek, Michael ; Huguet, Francoise ; Salek, Cyril ; Cabannes, Aurélie ; Wartiovaara-Kautto, Ulla ; Saillard, Colombe ; Raffoux, Emmanuel ; Cluzeau, Thomas ; Leprêtre, Stéphane ; Balsat, Marie ; Berceanu, Anna ; Boissel, Nicolas ; Clappier, Emmanuelle ; Morisset, Laure ; Gardin, Claude ; Dombret, Hervé ; Rousselot, Philippe</creator><creatorcontrib>Chevallier, Patrice ; Leguay, Thibault ; Doubek, Michael ; Huguet, Francoise ; Salek, Cyril ; Cabannes, Aurélie ; Wartiovaara-Kautto, Ulla ; Saillard, Colombe ; Raffoux, Emmanuel ; Cluzeau, Thomas ; Leprêtre, Stéphane ; Balsat, Marie ; Berceanu, Anna ; Boissel, Nicolas ; Clappier, Emmanuelle ; Morisset, Laure ; Gardin, Claude ; Dombret, Hervé ; Rousselot, Philippe</creatorcontrib><description>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.
[Display omitted]
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.
Inotuzumab ozogamicin as first line therapy in newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2021-148625</identifier><language>eng</language><publisher>Elsevier Inc</publisher><ispartof>Blood, 2021-11, Vol.138 (Supplement 1), p.511-511</ispartof><rights>2021 American Society of Hematology</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1425-1e70a7885d5ed80c2f71cf4a3b0aaaa102840aa92ee05e4d4e7a9bcb1344cd1a3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids></links><search><creatorcontrib>Chevallier, Patrice</creatorcontrib><creatorcontrib>Leguay, Thibault</creatorcontrib><creatorcontrib>Doubek, Michael</creatorcontrib><creatorcontrib>Huguet, Francoise</creatorcontrib><creatorcontrib>Salek, Cyril</creatorcontrib><creatorcontrib>Cabannes, Aurélie</creatorcontrib><creatorcontrib>Wartiovaara-Kautto, Ulla</creatorcontrib><creatorcontrib>Saillard, Colombe</creatorcontrib><creatorcontrib>Raffoux, Emmanuel</creatorcontrib><creatorcontrib>Cluzeau, Thomas</creatorcontrib><creatorcontrib>Leprêtre, Stéphane</creatorcontrib><creatorcontrib>Balsat, Marie</creatorcontrib><creatorcontrib>Berceanu, Anna</creatorcontrib><creatorcontrib>Boissel, Nicolas</creatorcontrib><creatorcontrib>Clappier, Emmanuelle</creatorcontrib><creatorcontrib>Morisset, Laure</creatorcontrib><creatorcontrib>Gardin, Claude</creatorcontrib><creatorcontrib>Dombret, Hervé</creatorcontrib><creatorcontrib>Rousselot, Philippe</creatorcontrib><title>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</title><title>Blood</title><description>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.
[Display omitted]
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.
Inotuzumab ozogamicin as first line therapy in newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia</description><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kU-P0zAQxQMCie7CB-A2d-TFdp1NCqeS3S6Voqbi7zFy7EljSOLKdlplPz1eypm5eCTr_d7TvCR5y-gNYzl_3_TWasIpZ4SJ_Janz5MFS3lOKOX0RbKglN4SscrYq-TK-1-UMrHk6eLZ1cZJFYwdZUAN29GG6XEaZAPVoz3IwSgzQmGHxozx-2xCB6U9k-0YcPQmzFB0ONjQoZPHGfbOnoxGDz_QzfAQE0E1BWUHhIipeo0O9jIYHIO_wHZ47me4M_IwWh8dijvO38G-M73U2B87I6ODs4P1EUJ2eIjqE8InUmDfRz9Uk_PWwVpNAaGch2Nnm176YBSUOP3GwcgPsDHOB_iCfuqjcRt5ECPD_c91WZLtroKvYdLz6-RlK3uPb_6918n3zf234jMpq4dtsS6JYoKnhGFGZZbnqU5R51TxNmOqFXLZUBmHUZ6LuK04Ik1RaIGZXDWqYUshlGZyeZ2wC1c5673Dtj46M0g314zWT2XWf8usn8qsL2VGzceLBmOwk0FXexXPqFCbeINQa2v-o_4DYg6tQg</recordid><startdate>20211123</startdate><enddate>20211123</enddate><creator>Chevallier, Patrice</creator><creator>Leguay, Thibault</creator><creator>Doubek, Michael</creator><creator>Huguet, Francoise</creator><creator>Salek, Cyril</creator><creator>Cabannes, Aurélie</creator><creator>Wartiovaara-Kautto, Ulla</creator><creator>Saillard, Colombe</creator><creator>Raffoux, Emmanuel</creator><creator>Cluzeau, Thomas</creator><creator>Leprêtre, Stéphane</creator><creator>Balsat, Marie</creator><creator>Berceanu, Anna</creator><creator>Boissel, Nicolas</creator><creator>Clappier, Emmanuelle</creator><creator>Morisset, Laure</creator><creator>Gardin, Claude</creator><creator>Dombret, Hervé</creator><creator>Rousselot, Philippe</creator><general>Elsevier Inc</general><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20211123</creationdate><title>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</title><author>Chevallier, Patrice ; Leguay, Thibault ; Doubek, Michael ; Huguet, Francoise ; Salek, Cyril ; Cabannes, Aurélie ; Wartiovaara-Kautto, Ulla ; Saillard, Colombe ; Raffoux, Emmanuel ; Cluzeau, Thomas ; Leprêtre, Stéphane ; Balsat, Marie ; Berceanu, Anna ; Boissel, Nicolas ; Clappier, Emmanuelle ; Morisset, Laure ; Gardin, Claude ; Dombret, Hervé ; Rousselot, Philippe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1425-1e70a7885d5ed80c2f71cf4a3b0aaaa102840aa92ee05e4d4e7a9bcb1344cd1a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chevallier, Patrice</creatorcontrib><creatorcontrib>Leguay, Thibault</creatorcontrib><creatorcontrib>Doubek, Michael</creatorcontrib><creatorcontrib>Huguet, Francoise</creatorcontrib><creatorcontrib>Salek, Cyril</creatorcontrib><creatorcontrib>Cabannes, Aurélie</creatorcontrib><creatorcontrib>Wartiovaara-Kautto, Ulla</creatorcontrib><creatorcontrib>Saillard, Colombe</creatorcontrib><creatorcontrib>Raffoux, Emmanuel</creatorcontrib><creatorcontrib>Cluzeau, Thomas</creatorcontrib><creatorcontrib>Leprêtre, Stéphane</creatorcontrib><creatorcontrib>Balsat, Marie</creatorcontrib><creatorcontrib>Berceanu, Anna</creatorcontrib><creatorcontrib>Boissel, Nicolas</creatorcontrib><creatorcontrib>Clappier, Emmanuelle</creatorcontrib><creatorcontrib>Morisset, Laure</creatorcontrib><creatorcontrib>Gardin, Claude</creatorcontrib><creatorcontrib>Dombret, Hervé</creatorcontrib><creatorcontrib>Rousselot, Philippe</creatorcontrib><collection>CrossRef</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chevallier, Patrice</au><au>Leguay, Thibault</au><au>Doubek, Michael</au><au>Huguet, Francoise</au><au>Salek, Cyril</au><au>Cabannes, Aurélie</au><au>Wartiovaara-Kautto, Ulla</au><au>Saillard, Colombe</au><au>Raffoux, Emmanuel</au><au>Cluzeau, Thomas</au><au>Leprêtre, Stéphane</au><au>Balsat, Marie</au><au>Berceanu, Anna</au><au>Boissel, Nicolas</au><au>Clappier, Emmanuelle</au><au>Morisset, Laure</au><au>Gardin, Claude</au><au>Dombret, Hervé</au><au>Rousselot, Philippe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Blood</jtitle><date>2021-11-23</date><risdate>2021</risdate><volume>138</volume><issue>Supplement 1</issue><spage>511</spage><epage>511</epage><pages>511-511</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><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.
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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.
Inotuzumab ozogamicin as first line therapy in newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia</abstract><pub>Elsevier Inc</pub><doi>10.1182/blood-2021-148625</doi><tpages>1</tpages></addata></record> |
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| title | 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 |
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