AUTHORS
Matteo Leoncin, MD, Sara Consolo2, Monia Lunghi3, Marco Cerrano, MD4, Davide Lazzarotto, MD5, Francesca Kaiser6, Gianluca Cavallaro7, Federico Lussana, MD, PhD8, Matteo Piccini, MD9, Erika Borlenghi, MD10, Antonino Mule', MD11, Mario Annunziata, MD12, Sabrina Mariani13, Giuseppe Lanzarone14, Massimiliano Bonifacio, MD15, Ilaria Tanasi16, Crescenza Pasciolla, MD17, Mario Delia, MD18, Lidia Santoro19, Marina Aurora Urbano20, Silvia Trappolini21, Ivana Lotesoriere Jr, MD22, Fabio Forghieri, MD23, Francesco Grimaldi, MD24, Davide Facchinelli25, Cristina Papayannidis, MD, PhD26, Carmela Gurrieri27, Mauro Endri28, Anna Candoni, MD29, Robin Foà, MD30, Sabina Chiaretti, MD31
AFFILIATIONS
1 Division of Hematology, Ospedale dell'Angelo, Venice, Italy
2 Division of Hematology, Ospedale dell'Angelo, Venice, Italy
3 Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont., Novara, Italy
4 Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Turin, Italy
5 Clinica Ematologica e Centro Trapianti, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
6 Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
7 Department of Oncology and Hematology, University of Milan and ASST Papa Giovanni XXIII, Bergamo, Italy
8 Department of Oncology and Hematology, University of Milan and ASST Papa Giovanni XXIII, Bergamo, Italy
9 Struttura Operativa Dipartimentale Hematology, Department of Hematology, Azienda Ospedale-Università (AOU) Careggi University, Florence, Italy
10 Division of Hematology, ASST Spedali Civili, Brescia, Italy
11 Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello, Palermo, Palermo, Italy
12 Hematology Unit, Cardarelli Hospital, Naples, Italy, Naples, Italy
13 Department of Hematology, University Hospital Sant'Andrea, Sapienza University of Rome,, Rome, Italy
14 Department of Oncology, Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Turin, Italy
15 Department of Engineering for Innovation Medicine, Section of Hematology, University of Verona, Verona, Italy
16 Department of Engineering for Innovation Medicine, Section of Hematology, University of Verona, Verona, Italy
17 UO Ematologia, IRCCS Oncologico Istituto Tumori Giovanni Paolo II, Bari, Italy
18 Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Bari, Italy
19 U.O.C. Ematologia e Trapianto di Midollo Osseo, Avellino, Italy
20 Ospedale “A. Perrino”, UOC Ematologia, Brindisi, Brindisi, Italy
21 Department of Hematology, AOU Ospedali Riuniti, Ancona, Italy
22 ASST Valle Olona, Ospedale Di Busto Arsizio, Busto Arsizio, Italy
23 Azienda Ospedaliero-Universitaria di Modena, Policlinico di Modena, Modena, Italy
24 Unità Operativa Complessa di Ematologia e Trapianto di Midollo Osseo, Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy
25 Hematology Department, Ospedale San Bortolo, Vicenza, Italy
26 IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy
27 Hematology Unit, Azienda Ospedale-Università and University of Padova, Padua, Italy
28 Hematology Unit, Ca' Foncello Treviso Hospital, Treviso, Italy
29 Hematology Unit, Ca' Foncello Treviso Hospital, Treviso, Italy
30 Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
31 Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
ABSTRACT
Background. Secondary acute lymphoblastic leukemia (sALL) is a rare malignancy defined as ALL arising in patients with a prior cancer. Given the low overall incidence of adult ALL, sALL remains understudied. Two distinct entities must be recognized: therapy-related ALL (tALL), arising after genotoxic treatments for a primary cancer, and an ALL following a prior malignancy (pmALL), occurring in patients without a prior exposure to chemo- and/or radiotherapy.
Methods. We retrospectively analyzed 179 adults with sALL - 134 tALLs and 45 pmALLs - diagnosed between December 2011 and December 2025 within the Campus ALL network in Italy. Categorical variables were compared using the χ2 test and overall survival (OS) was evaluated using the log-rank test.
Results. Baseline characteristics were similar between tALL and pmALL in terms of male/female ratio (90/89), median age (65 years, range 24–89), ECOG performance status, and Charlson Comorbidity Index (CCI). Significant differences emerged with regard to the prior primary malignancies. tALL was most frequently preceded by multiple myeloma (MM) and breast cancer (29 cases each, 21.6%), whereas pmALL was predominantly associated with urological cancers: 16 cases (35.5) vs 8 cases (6%) in tALL (p<0.001). All MM-associated tALL cases had prior immunomodulatory drug (IMiD) exposure.
Immunophenotypic characterization showed a B-lineage ALL in 149 cases (83.2%) and a T-lineage ALL in 30 (16.8%), equally distributed between tALL and pmALL. The presence of extramedullary disease at diagnosis, hyperleukocytosis, EGIL classification, karyotype, TP53 mutations, Ph-like signatures, and GIMEMA risk distribution (34.1% standard risk, 10.1% high risk, 35.2% very high risk) were comparable between tALL e pmALL, except for a higher proportion of Ph+ ALLs in pmALL (26.7% vs 14.2%; p=0.05).
Concerning induction strategies, excluding the 32 Ph+ ALL patients, we found no differences in treatment between tALL and pmALL patients: 63 (42.2%) patients received a pediatric-like regimen (42.2%), 12 received Hyper-CVAD (8.1%), 55 elderly adapted treatment (37.4%) and 18 palliative care only (12.2%).
Likewise, response and toxicity metrics were similar between tALL and pmALL in terms of complete remission (CR) rate (64.9% vs 71.1%), minimal residual disease negativity achievement (36.6% vs 35.6%), early death rate (8.2% vs 6.7%), grade 3–4 toxicities (49.3% vs 44.4%), and treatment interruption rate (34.3% vs 31.1%). An upfront allogeneic hematopoietic stem cell transplant was performed in 20% of pmALL vs 11.2% of tALL patients. Relapses occurred in 21.6% of tALL and in 31.1% of pmALL cases. Treatment-related mortality (TRM) was similar between tALL and pmALL (20.1% and 20% respectively), whereas death due to prior malignancy progression occurred in 1.5% of tALL and in 6.6% of pmALL cases.
A survival analysis of Ph- sALL patients was carried out and the results were compared to an independent cohort of 596 de novo Ph- ALL, selected from the Campus ALL historical database. This cohort had a younger median age (52 years, range 18-91) and 66% were treated with pediatric-like therapy. Overall, the 5-year OS was significantly lower in Ph- sALL compared to de novo Ph– ALL: 30.8% sALL vs 44.5% de novo ALL (p=0.0005). However, age-stratified analysis abolished this difference: 68.8% vs 63.4% (p=0.8) for patients <50 years, 29.3% vs 34% (p=0.3) for those aged 50–65 years, and 14.4% vs 21.1% (p=0.4) for those >65 years.
Conclusions. In our real-life series of sALL patients, we confirm that there is a strong correlation between treatment for MM and the development of ALL (all of B-lineage), probably due to clonal selection related to immunomodulant agents (all patients had been exposed to talidomide, lenalidomide or pomalidomide). Conversely, no definitive pattern emerged for other prior malignancies, likely confounded by the background population incidence and treatment heterogeneity. From an outcome perspective, tALL and sALL displayed CR rates, OS, and TRM comparable to those expected in elderly de novo ALL—a trend corroborated through our age-stratified de novo control cohort. Our findings suggest that the poor prognosis of sALL is not driven by intrinsic treatment refractoriness - as observed in secondary myeloid leukemias - but rather by advanced age and patient frailty onset. Further extensive molecular studies are needed to confirm this hypothesis.
DISCLOSURES
Sabina Chiaretti, MD: Gilead/Kite - Honoraria; Amgen - Honoraria; BeiGene - Honoraria; Pfizer - Honoraria; Incyte - Honoraria; Amgen - Consultancy (Includes expert testimony)