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FORTY MONTHS UPDATE OF THE GIMEMA LAL2116 (D-ALBA) PROTOCOL AND ANCILLARY LAL2217 STUDY FOR NEWLY DIAGNOSED ADULT PH+ ALL
Author(s): ,
Sabina Chiaretti
Affiliations:
Translational and Precision Medicine,Sapienza University of Rome,Rome,Italie;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italien;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italia;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italy;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italia;Translational a
,
Renato Bassan
Affiliations:
Hematology,Ospedale dell'Angelo,Venice,Italie;Hematology,Ospedale dell'Angelo,Venice,Italien;Hematology,Ospedale dell'Angelo,Venice,Italia;Hematology,Ospedale dell'Angelo,Venice,Italy;Hematology,Ospedale dell'Angelo,Venice,Italia;Hematology,Ospedale dell'Angelo,Venice,Italië;Hematology,Ospedale dell'Angelo,Venice,Itália;Hematology,Ospedale dell'Angelo,Venice,Италия;Hematology,Ospedale dell'Angelo,
,
Antonella Vitale
Affiliations:
Translational and Precision Medicine,Sapienza University of Rome,Rome,Italie;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italien;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italia;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italy;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italia;Translational a
,
Loredana Elia
Affiliations:
Translational and Precision Medicine,Sapienza University of Rome,Rome,Italie;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italien;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italia;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italy;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italia;Translational a
,
Alfonso Piciocchi
Affiliations:
GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus,Rome,Italie;GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus,Rome,Italien;GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus,Rome,Italia;GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus,Rome,Italy;GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus,Rome,Italia;GIMEMA Data Center,Fondazione GIMEM
,
Piera Viero
Affiliations:
Hematology,Ospedale dell'Angelo,Venice,Italie;Hematology,Ospedale dell'Angelo,Venice,Italien;Hematology,Ospedale dell'Angelo,Venice,Italia;Hematology,Ospedale dell'Angelo,Venice,Italy;Hematology,Ospedale dell'Angelo,Venice,Italia;Hematology,Ospedale dell'Angelo,Venice,Italië;Hematology,Ospedale dell'Angelo,Venice,Itália;Hematology,Ospedale dell'Angelo,Venice,Италия;Hematology,Ospedale dell'Angelo,
,
Felicetto Ferrara
Affiliations:
Hematology,Ospedale Antonio Cardarelli,Naples,Italie;Hematology,Ospedale Antonio Cardarelli,Naples,Italien;Hematology,Ospedale Antonio Cardarelli,Naples,Italia;Hematology,Ospedale Antonio Cardarelli,Naples,Italy;Hematology,Ospedale Antonio Cardarelli,Naples,Italia;Hematology,Ospedale Antonio Cardarelli,Naples,Italië;Hematology,Ospedale Antonio Cardarelli,Naples,Itália;Hematology,Ospedale Antonio C
,
Monia Lunghi
Affiliations:
Translational Medicine,University of Eastern Piedmont ,Novara,Italie;Translational Medicine,University of Eastern Piedmont ,Novara,Italien;Translational Medicine,University of Eastern Piedmont ,Novara,Italia;Translational Medicine,University of Eastern Piedmont ,Novara,Italy;Translational Medicine,University of Eastern Piedmont ,Novara,Italia;Translational Medicine,University of Eastern Piedmont ,
,
Francesco Fabbiano
Affiliations:
Hematology,Hospital Villa Sofia-cervello,Palermo,Italie;Hematology,Hospital Villa Sofia-cervello,Palermo,Italien;Hematology,Hospital Villa Sofia-cervello,Palermo,Italia;Hematology,Hospital Villa Sofia-cervello,Palermo,Italy;Hematology,Hospital Villa Sofia-cervello,Palermo,Italia;Hematology,Hospital Villa Sofia-cervello,Palermo,Italië;Hematology,Hospital Villa Sofia-cervello,Palermo,Itália;Hematolo
,
Massimiliano Bonifacio
Affiliations:
Medicine,Verona University,Verona,Italie;Medicine,Verona University,Verona,Italien;Medicine,Verona University,Verona,Italia;Medicine,Verona University,Verona,Italy;Medicine,Verona University,Verona,Italia;Medicine,Verona University,Verona,Italië;Medicine,Verona University,Verona,Itália;Medicine,Verona University,Verona,Италия;Medicine,Verona University,Verona,Italien
,
Nicola Fracchiolla
Affiliations:
Fondazione IRCCS ,Ca' Granda-Ospedale Maggiore Policlinico,Milan,Italie;Fondazione IRCCS ,Ca' Granda-Ospedale Maggiore Policlinico,Milan,Italien;Fondazione IRCCS ,Ca' Granda-Ospedale Maggiore Policlinico,Milan,Italia;Fondazione IRCCS ,Ca' Granda-Ospedale Maggiore Policlinico,Milan,Italy;Fondazione IRCCS ,Ca' Granda-Ospedale Maggiore Policlinico,Milan,Italia;Fondazione IRCCS ,Ca' Granda-Ospedale Ma
,
Paolo Di Bartolomeo
Affiliations:
Hematology, Transfusion Medicine and Biotechnologies,Ospedale Civile,Pescara,Italie;Hematology, Transfusion Medicine and Biotechnologies,Ospedale Civile,Pescara,Italien;Hematology, Transfusion Medicine and Biotechnologies,Ospedale Civile,Pescara,Italia;Hematology, Transfusion Medicine and Biotechnologies,Ospedale Civile,Pescara,Italy;Hematology, Transfusion Medicine and Biotechnologies,Ospedale Ci
,
Paola Fazi
Affiliations:
GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus,Rome,Italie;GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus,Rome,Italien;GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus,Rome,Italia;GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus,Rome,Italy;GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus,Rome,Italia;GIMEMA Data Center,Fondazione GIMEM
,
Maria Stefania De Propris
Affiliations:
Translational and Precision Medicine,Sapienza University of Rome,Rome,Italie;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italien;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italia;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italy;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italia;Translational a
,
Marco Vignetti
Affiliations:
GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus ,Rome,Italie;GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus ,Rome,Italien;GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus ,Rome,Italia;GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus ,Rome,Italy;GIMEMA Data Center,Fondazione GIMEMA – Franco Mandelli Onlus ,Rome,Italia;GIMEMA Data Center,Fondazione
,
Anna Guarini
Affiliations:
Molecular Medicine,Sapienza University of Rome,Rome,Italie;Molecular Medicine,Sapienza University of Rome,Rome,Italien;Molecular Medicine,Sapienza University of Rome,Rome,Italia;Molecular Medicine,Sapienza University of Rome,Rome,Italy;Molecular Medicine,Sapienza University of Rome,Rome,Italia;Molecular Medicine,Sapienza University of Rome,Rome,Italië;Molecular Medicine,Sapienza University of Rome
,
Alessandro Rambaldi
Affiliations:
Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII,Bergamo,Italie;Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII,Bergamo,Italien;Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII,Bergamo,Italia;Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII,Bergamo,Italy;Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni X
Robin Foà
Affiliations:
Translational and Precision Medicine,Sapienza University of Rome,Rome,Italie;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italien;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italia;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italy;Translational and Precision Medicine,Sapienza University of Rome,Rome,Italia;Translational a
(Abstract release date: 05/12/22) EHA Library. Chiaretti S. 06/10/22; 357216; P353
Dr. Sabina Chiaretti
Dr. Sabina Chiaretti
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P353

Type: Poster presentation

Session title: Acute lymphoblastic leukemia - Clinical

Background

The outcome of adult Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients greatly improved since the introduction of tyrosine kinase inhibitors (TKIs). A further improvement was achieved with a chemo-free induction/consolidation strategy based on the sequential administration of dasatinib followed by blinatumomab - the D-ALBA GIMEMA LAL2116 trial - with overall survival (OS) and disease-free survival (DFS) rates of 95% and 88% at 18 months (Foa et al, NEJM 2020).

Aims

To provide an updated follow-up of the D-ALBA trial and to document the long-term management of previously enrolled patients.

Methods

In the D-ALBA trial, after the primary endpoint, patients were followed for 12 months. Data on subsequent treatment and survival are being collected in the ancillary study GIMEMA LAL2217.

Results

As reported, 63 patients were enrolled (median age 54 years, 24-82; no upper age limit); the median follow-up is 40 months (0.9-62.5). Since enrollment in the D-ALBA trial, 9 relapses have been documented: 4 hematologic (1 major protocol deviation and 1 in an 82-year old woman who rapidly went off study), 4 at CNS and 1 nodal; median time to relapse was 4.4 months (1.9-25.8). Six deaths were recorded (3 post-allogeneic transplant) in 1st complete hematologic remission (CHR).

Of the 58 patients who started blinatumomab, 29 continued treatment with TKI: 21 with dasatinib (85% after receiving all 5 cycles of blinatumomab), 2 switched to imatinib due to intolerance (all after the 5 cycles of blinatumomab) and 5 switched to ponatinib for a molecular minimal residual disease increase or medical decision (66% had received all 5 cycles of blinatumomab). Twenty-nine patients were allografted, including 6 patients in 2nd CHR: 9 from a sibling, 13 from an unrelated donor, 6 from a haploidentical donor and 1 from a cord blood. Six transplants were performed in 2nd CHR. Before transplant, 8 patients received 2 and 3 cycles of blinatumomab, respectively, 5 4 cycles and 6 5 cycles (2 patients were allografted after 1 cycle). Among grafted patients, 6 deaths occurred, 3 of which in cases transplanted in 2nd CHR; thus, the transplant-related mortality in 1st CHR is 10%. When considered in a covariate model, transplant did not impact on both OS and DFS; similar results were obtained also considering allograft only in 1st CHR. It must, however, be underlined that the allografted population was enriched in cases who did not achieve a molecular response (23 pts). Further investigation is ongoing on this aspect. In the updated follow-up, the estimated 48 months OS is 78% (95% CI: 66-92%) and the DFS is 75% (95% CI: 64-87%). DFS was significantly better in patients achieving a molecular response upon induction than in those who did not (100% vs 67%, p=0.016, Fig. 1A), with no events recorded in the group of complete molecular responders and positive-not-quantifiable cases. Furthermore, we confirmed the inferior DFS for patients carrying an IKZF1plus genotype compared to that of cases with no IKZF1 deletions/IKZF1 deletions alone (85% vs 47%, p=0.012, Fig. 1B).

Conclusion
In the updated analysis of the D-ALBA trial and the ancillary GIMEMA LAL2217 study, with a median OS of 40 months, we confirm the reported very favorable outcome. Among the few relapsed cases, we observed a rather high incidence of CNS involvements. These results represent the scientific rationale for the ongoing phase 3 GIMEMA LAL2820 trial, where dasatinib has been substituted by ponatinib, CNS prophylaxis has been increased, and transplant allocation is based on genomic features and minimal residual disease monitoring.

Keyword(s): Follow-up, Immunotherapy, Philadelphia chromosome

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P353

Type: Poster presentation

Session title: Acute lymphoblastic leukemia - Clinical

Background

The outcome of adult Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients greatly improved since the introduction of tyrosine kinase inhibitors (TKIs). A further improvement was achieved with a chemo-free induction/consolidation strategy based on the sequential administration of dasatinib followed by blinatumomab - the D-ALBA GIMEMA LAL2116 trial - with overall survival (OS) and disease-free survival (DFS) rates of 95% and 88% at 18 months (Foa et al, NEJM 2020).

Aims

To provide an updated follow-up of the D-ALBA trial and to document the long-term management of previously enrolled patients.

Methods

In the D-ALBA trial, after the primary endpoint, patients were followed for 12 months. Data on subsequent treatment and survival are being collected in the ancillary study GIMEMA LAL2217.

Results

As reported, 63 patients were enrolled (median age 54 years, 24-82; no upper age limit); the median follow-up is 40 months (0.9-62.5). Since enrollment in the D-ALBA trial, 9 relapses have been documented: 4 hematologic (1 major protocol deviation and 1 in an 82-year old woman who rapidly went off study), 4 at CNS and 1 nodal; median time to relapse was 4.4 months (1.9-25.8). Six deaths were recorded (3 post-allogeneic transplant) in 1st complete hematologic remission (CHR).

Of the 58 patients who started blinatumomab, 29 continued treatment with TKI: 21 with dasatinib (85% after receiving all 5 cycles of blinatumomab), 2 switched to imatinib due to intolerance (all after the 5 cycles of blinatumomab) and 5 switched to ponatinib for a molecular minimal residual disease increase or medical decision (66% had received all 5 cycles of blinatumomab). Twenty-nine patients were allografted, including 6 patients in 2nd CHR: 9 from a sibling, 13 from an unrelated donor, 6 from a haploidentical donor and 1 from a cord blood. Six transplants were performed in 2nd CHR. Before transplant, 8 patients received 2 and 3 cycles of blinatumomab, respectively, 5 4 cycles and 6 5 cycles (2 patients were allografted after 1 cycle). Among grafted patients, 6 deaths occurred, 3 of which in cases transplanted in 2nd CHR; thus, the transplant-related mortality in 1st CHR is 10%. When considered in a covariate model, transplant did not impact on both OS and DFS; similar results were obtained also considering allograft only in 1st CHR. It must, however, be underlined that the allografted population was enriched in cases who did not achieve a molecular response (23 pts). Further investigation is ongoing on this aspect. In the updated follow-up, the estimated 48 months OS is 78% (95% CI: 66-92%) and the DFS is 75% (95% CI: 64-87%). DFS was significantly better in patients achieving a molecular response upon induction than in those who did not (100% vs 67%, p=0.016, Fig. 1A), with no events recorded in the group of complete molecular responders and positive-not-quantifiable cases. Furthermore, we confirmed the inferior DFS for patients carrying an IKZF1plus genotype compared to that of cases with no IKZF1 deletions/IKZF1 deletions alone (85% vs 47%, p=0.012, Fig. 1B).

Conclusion
In the updated analysis of the D-ALBA trial and the ancillary GIMEMA LAL2217 study, with a median OS of 40 months, we confirm the reported very favorable outcome. Among the few relapsed cases, we observed a rather high incidence of CNS involvements. These results represent the scientific rationale for the ongoing phase 3 GIMEMA LAL2820 trial, where dasatinib has been substituted by ponatinib, CNS prophylaxis has been increased, and transplant allocation is based on genomic features and minimal residual disease monitoring.

Keyword(s): Follow-up, Immunotherapy, Philadelphia chromosome

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