Therapy-Related Myeloid Neoplasms: Report Of The Italian Network On Secondary Leukemias
Authors: Fianchi Luana , Voso Maria Teresa , Candoni Anna , Gaidano Gianluca , Criscuolo Marianna , Specchia Giorgina , Pogliani Enrico Maria , Monarca Bruno , Maurillo Luca , Mecucci Cristina , Breccia Massimo , Aversa Franco , Musto Pellegrino , Rondoni Michela , Niscola Pasquale , Fozza Claudio , Invernizzi Rosangela , Spadea Antonio , Fenu Susanna , Buda Gabriele , Gobbi Marco , Santini Valeria , Mancini Stefano , Morra Enrica , Pagano Livio , Leone Giuseppe 
Published: October 2019

Abstract

Introduction
In 2001, the World Health Organization (WHO) recognized therapy-related myeloid neoplasms (t-MN) as a distinct entity including acute myeloid leukemia (AML) and myelodisplastic syndromes (MDS). At present, about 10% of all AML patients have a previous history of exposure to chemotherapy and/or radiation for a primary malignancy or autoimmune disease. In 2009, we initiated a Web-based epidemiological registry, with the purpose of collecting t-MN diagnosed at Italian Hematological or Oncological Divisions.

Methods
Demographic and clinical information on t-MN patients were included in the database whose access was restricted to selected users and was password-protected. Between May 2009 and June 2013, 279 t-MN patients [121 males and 158 females; median age 64 years (range 23-88 years)], observed at 22 Italian Centers between 1999 and 2012, were registered in the web-database.

Results
The primary malignancy (PM) was a hematological neoplasm (HM) in 123 cases (44%), a solid tumor in 145 cases (52%), and an autoimmune disease in 11 patients (4%). Twenty patients (7%) had a history of two or more previous cancers.
Among hematological malignancies, the most frequent PM were lymphoproliferative diseases (92/122 cases), while breast cancer (65/146 cases) was the most frequent primary solid tumor. In particular, hematological PM were: 92 lymphoprolipherative diseases (68 Non Hodgkin and 18 Hodgkin lymphoma, 6 chronic lymphocytic leukemia); 12 Multiple myeloma; 14 myeloproliferative neoplasms (7 Myelofibrosis; 3 polycitemia vera; 3 essential thrombocythemia; 1 Hypereosinophilic syndrome.); 1 Acute lymphoblastic leukemia; 4 Acute myeloid leukemia (acute promielocytic leukemia in 2 cases). Sites of primary solid tumors were: 65 Breast; 32 Uro-genital (14 prostate; 5 bladder; 8 uterus; 5 ovarium); 17 Colon-rectal; 8 Lung; 8 Thyroid; 15 others (2 stomach; 5 CNS; 2 skin, 4 oropharynx; 2 sarcoma). Eleven patients had previously received immunosuppressive therapy for an autoimmune disease (5 with mitoxantrone, 5 with methotrexate, 1 with chlorambucil).
Two-hundred-thirty-six patients had previously received chemotherapy for their primary malignancy, associated to radiotherapy (RT) in 94 cases. RT represented the only primary treatment in 43 cases. Median latency between PM and t-MN was 5.6 years (range 0.5-48). There were no differences between t-MN after lymphoprolipherative diseases or after breast cancer when considering patients’ age (p=0.09) or median latency (p 0.20) between PM and t-MN.
According to morphology, t-MN were classified as 164 AML, 108 MDS and 7 ALL. Karyotype was available for 204 patients and was unfavorable in 81 patients (complex in 54 patients including del(7) in 19 cases; 15 cases with isolated del(7)]. A recurrent chromosomal translocation was present in 13 patients [1 t(8;21), 8 t(15;17) and 1 inv(16); 3 t(9;22)], while 75 patients had a normal karyotype. One-hundred-thirty-five patients received chemotherapy for t-MN, while the hypomethylating drug Azacitidine was administered to 63 patients. Fifty-six patients underwent bone marrow transplantation (45 allogeneic and 11 autologous). Median OS from the t-MN diagnosis was 7.7 months (range 0.2-158+).

Conclusions
The incidence of t-MN is rising as a result of the increasing number of cancer survivors. Lymphoprolipherative diseases and breast cancer are the most common primary malignancies at risk of developing a therapy-related myeloid neoplasm.

Disclosures:
Santini: Novartis: Honoraria; Janssen : Honoraria; Celgene: Honoraria; gsk: Honoraria.