Final Analysis of the Italian Campus ALL Observational Study on 476 Older Patients with Philadelphia-Negative Acute Lymphoblastic Leukemia

Cerrano, Marco

Oral and Poster Abstracts
Oral
906. Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: 'In with the Old, In with the New': Outcomes of Conventional and Novel Therapeutic Paradigms in Aggressive Lymphoid Malignancies

Research, Lymphoid Leukemias, ALL, Elderly, Clinical Research, Diseases, Real-world evidence, Lymphoid Malignancies, Study Population, Human, Measurable Residual Disease

Marco Cerrano, MD^1,2^*, Lazzarotto Davide, MD³^*, Eleonora Boscaro⁴^*, Erika Borlenghi, MD⁵^*, Ilaria Tanasi, MD⁶^*, Patrizia Chiusolo, MD, PhD⁷^*, Paola Minetto, MD, PhD⁸^*, Francesco Grimaldi, MD, PhD⁹^*, Michelina Dargenio¹⁰^*, Matteo Leoncin¹¹^*, Silvia Trappolini¹²^*, Cristina Papayannidis, MD, PhD¹³^*, Fabio Forghieri¹⁴^*, Carmela Gurrieri, MD¹⁵^*, Patrizia Zappasodi¹⁶^*, Roberta La Starza, MD¹⁷^*, Nicola Fracchiolla¹⁸^*, Federica Di Biase, MD¹⁹^*, Maria Ilaria Del Principe²⁰^*, Marzia Defina²¹^*, Crescenza Pasciolla²²^*, Benedetta Cambò²³^*, Federico Mosna²⁴^*, Daniela Pietrasanta²⁵^*, Sabrina Mariani²⁶^*, Valentina Mancini, MD²⁷^*, Fabio Guolo, MD, PhD²⁸, Federico Lussana²⁹^*, Elisabetta Todisco³⁰^*, Mario Annunziata, MD³¹^*, Valeria Calafiore³²^*, Maria Ciccone³³^*, Matteo Piccini³⁴^*, Matteo Emidio Dragani, MD³⁵^*, Beatrice Sani³⁶^*, Endri Mauro³⁷^*, Claudia Basilico³⁸^*, Beatrice De Marco³⁹^*, Marco Antonacci⁴⁰^*, Laura Forlani⁴¹^*, Monica Fumagalli, MD⁴²^*, Fabio Trastulli, MD⁴³^*, Monia Lunghi⁴⁴^*, Prassede Salutari⁴⁵^*, Sara Mastaglio, MD⁴⁶^*, Sabina Chiaretti, MD, PhD⁴⁷, Anna Candoni⁴⁸^*, Felicetto Ferrara, MD⁴⁹^*, Giovanni Pizzolo, MD⁵⁰^*, Robin Foà, MD⁴⁷^* and Massimiliano Bonifacio, MD⁵¹^*

¹SC Ematologia AOU Città della Salute e della Scienza, Torino, To, Italy
²Hematology, Department of Hematology and Oncology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy
³Clinica Ematologica e Centro Trapianti, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
⁴Division of Hematology, Department of Oncology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy
⁵ASST Spedali Civili, Brescia, Department of Hematology, Brescia, Italy
⁶Division of Hematology, Departemnt of Medicine, Policlinico G.B.Rossi - AOUI Verona, Verona, ITA
⁷UOC Ematologia e Trapianto Cellule Staminali Emopoietiche, Fondazione Policlinico Universitario A. Gemelli IRCCS Roma, Rome, Italy
⁸U.O. Clinica Ematologica, IRCCS. A.O.U.San Martino-IST, Genova, ITA
⁹Department of Clinical Medicine and Surgery, Hematology Unit, University of Naples Federico II, Napoli, Italy
¹⁰Hematology and Stem Cell Transplantation Unit, Vito Fazzi Hospital, Lecce, Italy
¹¹Azienda Ulss3 Serenissima,Hematology Unit, Ospedale dell'Angelo, Venezia, Italy
¹²S.O.D. Clinica Ematologica, Azienda Ospedaliero Universitaria delle Marche, Ancona, ITA
¹³S. Orsola-Malpighi Polyclinic, Bologna, ITA
¹⁴Universisty of Modena and Reggio Emilia, Modena, ITA
¹⁵Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
¹⁶Hematology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
¹⁷Hematology, CREO, Centro Ricerche Emato-Oncologiche, University of Perugia, Perugia, Italy
¹⁸Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
¹⁹Department of Molecular Biotechnology and Health Sciences, Division of Hematology, University of Torino, Torino, Italy
²⁰Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
²¹Hematology and Transplantation, Siena, ITA
²²Ematologia, Istituto Tumori Giovanni Paolo II- Bari, Bari, Italy
²³U.O.C. Ematologia e Centro Trapianti Midollo Osseo, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
²⁴Azienda Sanitaria dell'Alto Adige, Bolzano, ITA
²⁵Division of Hematology, Azienda Ospedaliera SS Arrigo E Biagio E Cesare Arrigo, Alessandria, ITA
²⁶Hematology Unit, Azienda Ospedaliera Universitaria Sant'Andrea, Sapienza University, Rome, ITA
²⁷Department of Hematology and Oncology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
²⁸Hematology Unit, Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy
²⁹Department of Oncology and Hematology, University of Milan and ASST Papa Giovanni XXIII, Bergamo, Italy
³⁰Hematology and Stem Cell Transplantation Division, European Institute of Oncology, Milan, Italy
³¹Hematology, San Giuseppe Moscati Hospital, Aversa, Italy
³²Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello, Palermo, ITA
³³Hematology Section, Department of Medical Sciences, AOU Arcispedale S.Anna, Ferrara, Italy
³⁴SOD Ematologia, Università di Firenze, AOU Careggi, Firenze, Italy
³⁵Ematologia, IRCCS AOU San Martino-IST, Genova, Italy
³⁶S.C.D.U. Ematologia, A. O. Ordine Mauriziano di Torino, Torino, Italy
³⁷Ospedale Ca' Foncello, TREVISO, ITA
³⁸Hematology Unit, ASST Sette Laghi-Ospedale di Circolo di Varese e Fondazione Macchi, Varese, Italy
³⁹UO Ematologia, ASST Spedali Civili di Brescia, Brescia, Italy
⁴⁰Div. of Hematology, Dept. of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy
⁴¹Hematology Unit, Azienda Ospedale-Università Padova (AOPD), Padua, Italy
⁴²Hematology Division and Bone Marrow Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
⁴³Ematologia, AORN A. Cardarelli, Napoli, Napoli, ITA
⁴⁴Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
⁴⁵Presidio Ospedaliero Pescara, Pescara, ITA
⁴⁶Hematology and Bone Marrow Transplant, Unit San Raffaele Scientific Institute, Milano, Milano, Italy
⁴⁷Department of Translational and Precision Medicine, Division of Hematology, Sapienza University, Rome, Italy
⁴⁸Hematology Unit, Section of Haematology, Dept. of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Modena, Italy
⁴⁹Division of Hematology, AORN Cardarelli, Naples, Napoli, Italy
⁵⁰Department of Engineering for Innovation Medicine, Section of Hematology, University of Verona, Verona, Italy
⁵¹Department of Engineering for Innovation Medicine, Section of Innovation Biomedicine, Hematology Area, University of Verona, Verona, Italy

BACKGROUND

The prognosis of younger Philadelphia (Ph)-negative acute lymphoblastic leukemia (ALL) patients (pts) has significantly improved in recent years, but older adults still experience poor outcomes with standard chemotherapy. Recent GMALL data suggested that dose-reduced regimens including asparaginase (ASP) are feasible in older pts with encouraging survival, warranting confirmation. Immunotherapy has changed the treatment landscape of B-ALL, but long-term overall survival (OS) remains poor when these therapies are employed in the relapsed/refractory setting. Indeed, these agents are being moved front-line, but they are not widely available in this setting yet.

METHODS

In the context of the Campus ALL national framework, we retrospectively collected data on Ph-negative ALL pts aged ≥55y diagnosed between January 2013 and December 2023 in Italy. Kaplan-Meier, Cox proportional hazard methods and competitive risk analyses were performed with STATA 12.1 to estimate survival outcomes and cumulative incidence functions.

RESULTS

We included 476 pts (female 52%), with a median age of 66y (range 55-91y), 31% > 70y. 78% of the cases were B-lineage, 39% were very high risk (VHR) according to LAL1913 classification, 5% showed central nervous system (CNS) infiltration and 33% had an ECOG performance status (PS) ≥2.

Eight pts received palliative care only (not analyzed for outcomes) while most pts (98%) started an active treatment according to different regimes with frequent dose adaptations: 53% LAL1913/NILG10.07, 17% LAL1104, 8% EWALL/GMALL, 6% Hyper-CVAD/mini-HyperCVD, 2% vincristine and steroids, 14% others. During the disease course, 31% of the pts received immunotherapy and 23% an allogeneic stem cell transplant.

After a median follow up of 42.9m, median OS was 21.3m, with a 3y-OS rate of 40%. 30- and 60-day mortality rates were 4% and 9%, respectively. After induction (course I or II) complete remission (CR)/CR with incomplete count recovery (CRi) rate was 76%, in 35% of the cases with a negative measurable residual disease (MRD), while 8% of the pts died before response assessment. After achieving remission, 47% of the pts relapsed and 13% died in remission, with a median relapse free survival (RFS) of 17.1m and a 3y-RFS rate of 40%. 3y-cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 50% and 10%.

Over time, a modest improvement of survival was observed, with pts diagnosed after 2017 showing superior OS (median 23.1 vs 18.1m, P=0.045), mostly in B-ALL (median 26.4 vs 18m, P=0.058, compared to 14.9 vs 18.1m, P=0.64, for T-ALL).

Age was a strong prognostic factor (HR 1.05, P<0.001), with pts aged 55-70y showing significant superior OS compared to those >70y (median 27.9 vs 11.2m, P<0.001) and a higher CR/CRi rate (81% vs 66%, P<0.001).

After adjusting for age and PS, treatment regimens including ASP (LAL1913/NILG10.07 and EWALL/GMALL) were superior to other approaches (HR 0.58, P<0.0001). However, this benefit was not significant in pts aged >70y (HR 0.65, P=0.09).

At multivariate analysis, age (HR 1.04, P<0.001), VHR group (HR 1.43, P=0.007), and CNS positivity (HR 2.9, P<0.001) were significantly associated with worse survival, while ASP-containing regimens with better outcome (HR 0.63, P=0.003).

MRD negativity was independently associated with improved RFS (HR 0.51, P<0.001) and reduced CIR (sHR 0.48, P<0.001). However, relapses were quite frequent (27% of the pts). Considering the 71 MRD-negative B-ALL pts up to 70y, our results were comparable to those observed in the standard arm of the E1910 clinical trial (3y-RFS 54% vs 57%).

CONCLUSION

In this large real-life cohort of older Ph-negative ALL pts, ASP-containing regimens appeared superior to other approaches after accounting for age and PS, but this benefit was markedly reduced above 70y. Only modest survival improvements were observed in recent years and restricted to B-ALL, possibly due to the increasing availability of salvage immunotherapies. MRD negativity was associated with better prognosis, but relapses were rather frequent, confirming the need of new drugs also in this setting. Different front-line therapeutic strategies, such as immunotherapy combined with minimal/no chemotherapy, are currently being tested in clinical trials for older B-ALL pts and are especially warranted in those above 70y. Hopefully, innovative trials will be starting soon in T-ALL, in which new drugs are currently lacking.

Disclosures: Cerrano: Italfarmaco: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Other: Educational activity ; Servier: Honoraria, Other: Educational activity ; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Other: Educational activity ; Astellas: Other: Educational activity ; Janssen: Other: Educational activity ; Jazz: Other: Educational activity ; Pfizer: Other: travel support. Borlenghi: Abbvie: Consultancy; Incyte: Other: Travel Grant; BMS: Consultancy; Amgen: Other: Travel Grant. Papayannidis: Novartis: Honoraria; Blueprint: Honoraria; GSK: Honoraria; Incyte: Honoraria; Amgen: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Menarini/Stemline: Honoraria; Astellas: Honoraria; Abbvie: Honoraria. Zappasodi: Amgen: Honoraria; pfizer: Consultancy, Honoraria; astellas: Honoraria; Abbvie: Honoraria. Fracchiolla: Amgen: Speakers Bureau; Jazz: Speakers Bureau; Abbvie: Speakers Bureau; Pfizer: Speakers Bureau. Lussana: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Clinigen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chiaretti: Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Candoni: BMS: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; Incyte: Honoraria; Janssen: Honoraria. Bonifacio: BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

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113 Final Analysis of the Italian Campus ALL Observational Study on 476 Older Patients with Philadelphia-Negative Acute Lymphoblastic Leukemia