CPX-351 is a feasible bridge to allogeneic hematopoietic stem cell transplantation in TP53 mutated acute myeloid leukemia with myelodisplastic related changes or therapy related without del(17p): Sub-analysis from a large italian real world retrospective study
Abstract
Abstract CPX-351 has been approved for Acute Myeloid Leukemia (AML) with myelodysplasia related changes (AML-MRC) and therapy-related (t-AML) induction. The likelihood of TP53 mutations (TP53m) in this setting is 20-35% but, considering the many variables of TP53m topography and configuration, the assessment of the prognostic impact of TP53 lesions may be challenging. This is the largest subanalysis about the outcome of TP53m AML-MRC and t-AML patients (pts) homogeneously treated with CPX-351 and has been conducted between January 2019 and December 2021 within the italian retrospective real world study about 513 pts (Guolo F. and Todisco E., paper submitted to American Journal of Hematology). Over 335 evaluable pts, in 51 (15%), 39 AML-MRC and 12 t-AML, TP53m were detected by Sanger (n=5) or Next Generation Sequencing (n=28) analysis or both (n=18). Median age was 63 years (range 23-73). Among the 286 TP53 wild-type pts (TP53w), 162 (57%) had complex karyotype (CK) and 10 (3%) del(17p) (9 of which in the context of CK) while, among the 51 TP53m pts, CK was found in 29 (57%) and del(17p) in 6 (12%) (5 of which with CK). According to Grob T. et al., Blood 2022, 26 of 50 evaluable TP53m pts (51%) were classified as biallelic. We also analysed the TP53m population according to Bahaj W. et al., Journal of Hematology & Oncology 2023 (applicable in 40 pts) finding substantial overlap in the assignment of allelic status. According to both classifications, a CK was significantly more frequent among biallelic mutated pts: 22 CK/26 biallelic mutated pts (85%), vs 6/24 (25%) among monoallelic (p<0.05) while all pts with a del(17p) had a biallelic mutation. Twenty-four of 51 TP53m pts (47%) and 162 of 286 TP53wt pts (57%) obtained complete remission or complete remission with incomplete hematologic recovery (CR/CRi) (p .096). In multivariate analysis for CR considering molecular and cytogenetic characteristics including allelic TP53 status, del(17p) resulted the only variable with independent negative prognostic impact (p .018, HR 1.05-1.55). In fact, among the 6 pts with del(17p), none achieved CR. Overall, 122/286 (43%) TP53wt pts and 15/51 (29%) of the TP53m cohort underwent allogeneic stem cell transplantation (allo-SCT). Among the 15 TP53m transplanted pts, 40% (n=6) had a biallelic mutation, 33% (n=5) had CK (but none with del(17p). After a median follow up of 23,67 months (m) (CI 95% 21.47-25.86), median OS (mOS) of the TP53w population was 17,1 m (range 16.7-20.27) vs 9,5 m (range 6.8-12.4) for TP53m, p .064; no significative difference but a trend was observed between TP53w and TP53 mono vs biallelic (mOS 17.1 m and 18.53 m vs 8.2 m respectively, p .110). We have therefore performed analyses based on the presence of CK: mOS was 19,3 m for TP53w pts without CK and 14,6 m for those carrying CK (p .117) vs respectively 32,5 m and 11,5 m (p .053) within TP53m cohort. A CK was not significantly related to a worse survival regardless of allelic status (mOS not reached and 10.3 m for pts without CK with mono and biallelic mutation vs respectively 4.7 m and 7.9 m for those with CK, p .496). Within the TP53m cohort, the presence of a missense TP53m vs other mutations (frameshift, nonsense, splice or intronic) resulted in non significant survival difference (p .213) as between canonical or non canonical missense TP53m (p .265). Furthermore, we did not find any impact on survival when we considered co-mutations (available only in 35 of 51 TP53m pts), their number or combinations. Del(17p) was instead the only factor having a negative impact on survival (mOS 4,7 m with del(17p) vs 13,6 m without, p.005). In a landmark analysis of TP53m pts alive and in 1st CR at 3 m who underwent allo-SCT (n=15, 62% of those achieving CR), mOS was not reached vs 10,3 m for not transplanted pts (p .347). We were unable to perform further subanalyses in this context because of the small population size. Although the incidence of TP53 mutations is likely underestimated due to the retrospective nature of the study, our analysis shows that CPX-351 is a feasible therapeutic option as bridge to allo-SCT also in a difficult subset like TP53m AML-MRC and t-AML unless if del(17p) is also present. We are conducting a retrospective and prospective expansion of the study in order to verify our findings on a larger sample size.
Article Details
Authors (51)
Elisabetta Todisco
15SC Ematologia, Ospedale “Busto Arsizio”, ASST Valle Olona, Varese, Italy
Ivana Lotesoriere
1ASST-Valle Olona-Busto Arsizio, Varese, BUSTO ARSIZIO, Italy
Federico Lussana
1ASST Papa Giovanni XXIII, Bergamo, Italy
Valentina Mancini
7ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
Federica Gigli
14Divisione di Oncoematologia, IRCCS Istituto Europeo di Oncologia., Milano, Italy
Cristina Papayannidis
2IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy
Michela Rondoni
6Hematology Unit, Ravenna Hospital, University of Bologna, Ravenna, Italy
Felicetto Ferrara
8“A. Cardarelli” Hospital, Naples, Italy
Sara Mastaglio
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Annalina Piccioni
10San Giovanni Addolorata Hospital, Rome, Italy
Michelina Dargenio
16Hematology and Stem Cell Transplant Unit, “Vito Fazzi” Hospital, Lecce, Italy
Andrea Corbingi
12“Santa Maria Goretti” Hospital, Latina, Italy
Francesco Mannelli
1SOD Ematologia, Università di Firenze, AOU Careggi, Firenze, Italy
Alessandro Cignetti
14A. O. “Ordine Mauriziano”, Turin, Italy
Patrizia Zappasodi
7Dipartimento di Oncoematologia, Fondazione IRCCS Policlinico San Matteo., Pavia, Italy
Maria Paola Martelli
18Ematologia e Immunologia Clinica, Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, e Azienda Ospedaliera ‘Santa Maria della Misericordia ‘ di Perugia, Perugia, Italy
Monia Lunghi
15Division of Hematology, Department of Translational Medicine, AOU Maggiore della Carità, University of Eastern Piedmont, Novara, Italy
Luana Fianchi
8Dipartimento Di Diagnostica Per Immagini, Fondazione Policlinico Universitario A. Gemelli, IRCCS- Università Cattolica del Sacro Cuore, Radioterapia Oncologica Ed Ematologia, Roma, Italy
Patrizia Chiusolo
6Section of Hematology, Department of Radiological and Hematological Sciences, Catholic University, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
Francesco Grimaldi
7AOU Federico II, Dipartimento di Medicina Clinica e Chirurgia, Napoli, Italy
Federica Pilo
6Azienda Ospedaliera Brotzu, Cagliari, Italy
Carla Fili
9Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), PO “S.Maria della Misericordia”, SOC Clinica Ematologica, Centro Trapianti e Terapie Cellulari, Udine, Italy
DEBORA CAPELLI
16Hematology Department, University of Ancona, Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy., ANCONA, Italy
Massimo Breccia
25Hematology, Department of Translational and Precision Medicine, Azienda Policlinico Umberto I, Sapienza University, Rome, Italy
Monica Bocchia
1Hematology Unit, University of Siena, Siena, Italy
Monica Fumagalli
Sara Galimberti
14Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
Luca Maurillo
23Department of Biomedicine and Prevention, University of Rome tor Vergata, Rome, Italy
Calogero Vetro
1Hematology and Bone Marrow Transplantation Unit, Hospital of Bolzano (SABES-Azienda Sanitaria dell'Alto Adige), Teaching Hospital of Paracelsus Medical University, Bolzano, Italy
Alessandra Sperotto
3Onco Hematology, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
Caterina Patti
21“Villa Sofia – Cervello” Hospital, Palermo, Italy
Erika Borlenghi
10ASST Spedali Civili of Brescia, Department of Hematology, Brescia, Italy
Federica Lessi
7Ematologia E Immunologia, Clinica Azienda Ospedaliera Di Padova, Padova, Italy
Alessandro Isidori
7AORMN Hospital, Pesaro, Italy
Raffaele Palmieri
11Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
Caterina Alati
2“Bianchi-Melacrino-Morelli” Hospital REGGIO CALABRIA, Reggio Calabria, Italy
Samuele Gatani
1ASST Valle Olona, Busto Arsizio, Italy
Chiara Pessina
22SSD Specialized Laboratory of Medical Genetics, Cytogenetics and Medical Genetics, ASST Sette Laghi, Ospedale di Circolo, Varese, Italy
Paola Minetto
12Clinic of Hematology, Department of Internal Medicine, University of Genova, Genova, Italy
Carola Riva
1University of Genoa, Clinic of Hematology, Department of Internal Medicine, Genoa, Italy
Marco Frigeni
1ASST Papa Giovanni XXIII, Bergamo, Italy
Nicola Stefano Fracchiolla
6IRCCS Ca'Granda “Ospedale Maggiore Policlinico di Milano”, Milano, Italy
Carla Mazzone
40Hematology Unit, Sant'Eugenio Hospital, Rome, Italy
Marco Cerrano
7S.C. Ematologia, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza-Presidio Molinette, Turin, Italy
Massimo Bernardi
Michele Gottardi
30IOV “Venetian Oncology Institute” IRCCS, Castelfranco Veneto, Italy
Roberto Cairoli
10ASST Grande Ospedale Metropolitano Niguarda, SC Ematologia, Milano, Italy
Adriano Venditti
23Department of Biomedicine and Prevention, University of Rome tor Vergata, Rome, Italy
Livio Pagano
8Dipartimento Di Diagnostica Per Immagini, Fondazione Policlinico Universitario A. Gemelli, IRCCS- Università Cattolica del Sacro Cuore, Radioterapia Oncologica Ed Ematologia, Roma, Italy
Roberto Lemoli
Fabio Guolo
12Clinic of Hematology, Department of Internal Medicine, University of Genova, Genova, Italy