Intervento della Dott.ssa Serena Merante, Haematology Consultant James Cook University Hospital Middlesbrough, UK al Convegno dell'Associazione Italiana Pazienti Leucemia Mieloide Cronica del 20 Maggio 2017 presso Triuggio (Mb)

1. Rischio di secondi
tumori nella LMC
Serena Merante
James Cook University Hospital, Middlesbrough, UK

2. • 2005 Jul;90(7):979-81.
Outcome of four patients with chronic
myeloid leukemia after
imatinib mesylate discontinuation.
Merante S, Orlandi E, Bernasconi P, Calatroni S, Boni M, Lazzarino M

3. Rischio di secondi tumori e LMC
• Il rischio è legato alla mia malattia
(LMC)?
• Il rischio è aumentato dalla terapia che sto
facendo?
• Il rischio è uguale a tutte le età?
• Si può PREVENIRE un secondo tumore?
• Si può curare un secondo tumore?
• Posso continuare a curarmi per la LMC e
anche per un secondo tumore?

4. Chronic myelogenous leukemia and exposure to ionizing
radiation--a retrospective study of 443 patients.
Corso A, Lazzarino M, Morra E, Merante S, Astori C, Bernasconi P, Boni M, Bernasconi C. .
Annals of hematology Volume: 70 Issue 2 (1995)
• We performed a retrospective study of 443 consecutive CML
patients, looking for a history of significant exposure to Rx,
and evaluated the clinical and hematological characteristics in
order to find any difference between radiation-related CML
patients and those with de novo CML
• In conclusion, this study of a large cohort of CML patients
indicates that the subgroup of patients with a history of
significant exposure to ionizing radiation has particular
clinical and hematological features at onset (lower tumor
burden, higher frequency of anemia) and a better survival.

5. Messaggio
Un sottogruppo di pazienti con una
storia di significativa esposizione a
radiazioni ionizzanti ha particolari
caratteristiche:
• Bassa “massa tumorale”
• Anemia
• Migliore sopravvivenza

6. American Journal of Epidemiology
ª Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public
Health. September 22, 2010
Are Chronic Myeloid Leukemia Patients More at Risk for Second Malignancies?
A Population-based Study
Paola Rebora, Kamila Czene, Laura Antolini, Carlo Gambacorti Passerini, Marie Reilly, and MariaGrazia
Valsecchi*
• To assess the incidence rate of second primary cancers among chronic
myeloid leukemia (CML) patients and the long-term survival of CML patients
before the introduction of tyrosine kinase inhibitors.
• Swedish Cancer Registry, 2,753 adult CML patients diagnosed between 1970
and 1995 who were followed through December 2007. Standardized incidence
ratios (SIRs) and relative survival ratios were computed.
• With a total of 145 subsequent primary malignancies, an increased incidence
rate of second malignancy was found for stomach cancer (SIR ¼ 2.76, 95%
confidence interval (CI): 1.33,5.08), skin cancer (SIR ¼ 5.36, 95% CI: 3.18, 8.47),
urogenital tract cancer (SIR ¼ 1.61, 95% CI: 1.15, 2.21), and lymphoid leukemia
(SIR ¼ 5.53, 95% CI: 1.79, 12.89).
• Long-term relative survival figures showed that CML was related, in the era
prior to the introduction of imatinib, to a very steep decline in survival (2 years
from diagnosis,relative survival ¼ 51%, 95% CI: 49, 53). This was in spite of a
marginal improvement after 1985, possibly related to the introduction of
interferon-a for treatment.
• Relevant reference for future studies and a benchmark for comparisons with
prognosis in CML patients after chronic use of tyrosine kinase inhibitors.

7. Prima dell’introduzione della terapia con
inibitori delle tirosinchinasi
• Una maggiore incidenza di secondi
tumori
• Una caduta della curva della
sopravvivenza (a 2 anni dalla diagnosi)
• Studio base per studi futuri di
confronto fra “prima” e “dopo” TKIs

8. From: Are Chronic Myeloid Leukemia Patients More at Risk for Second Malignancies? A Population-based
Study
Am J Epidemiol. 2010;172(9):1028-1033. doi:10.1093/aje/kwq262
Am J Epidemiol | American Journal of Epidemiology © The Author 2010. Published by Oxford University Press on behalf of the
Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail:
journals.permissions@oxfordjournals.org.

9. Chronic myeloid leukemia and risk of second malignancy
in two eras of treatment
Brady L. Stein Leukemia & Lymphoma 2012
” …the evidence is stronger for this association in the “pre-
imatinib era”
Clearly, the issue of secondary cancer in CML is complex, various factors:
- cumulative treatment, possibly when radiation,
hydroxyurea or busulfan are utilized
- immunodefciency,
- lifestyle choices, particularly smoking,
- aging,
- genetic predisposition

10. Rischio di seconde neoplasie nelle due ere di
trattamento
• Il rischio è più significativo nella “pre-imatinib era”
• L’argomento è complesso e deve tenere conto di vari
fattori
• Il trattamento cumulativo spesso venivano utlizzate
associazioni (radiazioni, idrossiurea,busulfano, altra
chemioterapia)
• Alterazioni del sistema immunitario
• Stile di vita (fumo, alcool, dieta)
• Età
• Predisposizione genetica

11. Second malignancies following treatment of chronic
myeloid leukaemia in the tyrosine kinase inhibitor era
British Journal of Haematology, 2015, 169, 683–688
• Founded on a population-based material, our
results indicate that CML patients treated in
the TKI era are at an increased risk of
developing a second malignancy, with
indications that this risk may more likely be
linked to CML itself rather than to the TKI
treatment.

12. Second malignancies following treatment of chronic myeloid
leukaemia in the tyrosine kinase inhibitor era
British Journal of Haematology, 2015, 169, 683–688
• Le persone trattate con TKIs hanno un
aumentato rischio di seconde
neoplasie
• Il rischio tuttavia è più verosimilmente
legato alla LMC “per se”piuttosto che
al trattamento con TKIs.

13. Clin Lymphoma Myeloma Leuk. 2016 Oct;16(10):577-581. doi: 10.1016/j.clml.2016.06.010.
Incidence of Second Malignancies of Chronic Myeloid Leukemia During
Treatment With Tyrosine Kinase Inhibitors.
Yin XF1, Wang JH2, Li X1, Yu MX1, Ma ZX1, Jin J3.
• BACKGROUND: Tyrosine kinase inhibitors (TKIs) have revolutionized the
treatment of chronic myeloid leukemia (CML) by providing patients with
long-term survival. Although most patients who receive TKI treatment have
shown satisfactory tolerance, second malignancies (SMs) should not be
ignored because of lifetime treatment. We designed a retrospective study to
evaluate the incidence and possible risk factors of SMs in CML patients
treated with TKIs.
• PATIENTS AND METHODS: Records of 223 patients with Philadelphia chromosome-positive CML treated
with imatinib were reviewed to investigate frequencies and characteristics of SMs. The data of SMs were
compared with the number expected from the National Central Cancer Registry. The possible risk factors
of SM in CML patients treated with TKIs were also evaluated using Poisson regression in this study.
• RESULTS:After a median follow-up of 64 months (range, 4-253 months) from CML diagnosis,
7 patients (3.14%) developed 6 different SMs including colon, stomach, breast, kidney,
cervical, and lymphonodus tissue. The risk of second cancer was higher than expected
(observed-to-expected ratio, 2.45; 95% confidence interval, 1.17-5.14; P = .018). No
associated elements were found in terms of influencing the incidence of SM in CML patients
treated with TKIs.
• CONCLUSION: We found patients with CML treated with TKIs had a higher
relative incidence of SM compared with the expected incidence among the
general Chinese population. However, the correlations between second
cancer and the potential risk factors including the length of exposure and
cumulative dose of TKIs were not found in this study.

14. Clin Lymphoma Myeloma Leuk. 2016 Oct;16(10):577-581. doi:
10.1016/j.clml.2016.06.010. Incidence of Second Malignancies of Chronic
Myeloid Leukemia During Treatment With Tyrosine Kinase Inhibitors.
Yin XF1, Wang JH2, Li X1, Yu MX1, Ma ZX1, Jin J3.
• Poiché il trattamento dura tutta la vita il
rischio di seconde neoplasie non può
essere ignorato
• Tuttavia le correlazioni tra seconde
neoplasie ed il potenziale rischio di
fattori come la durata del trattamento
con TKIs e la dose cumulativa non è
risultata statisticamente significativa.

15. Warnings…
• Because of improving survival and
longevity, age-appropriate cancer
screening should play a signifcant role in
the care of the patient with CML, but the
current literature cannot implicate imatinib
as a culprit in second cancer risk.

16. Chi è il colpevole?
• Allungamento della vita media-longevità
• Fattori genetici
• Stile di vita (FUMO,ALCOOL, OBESITA’,
DIETA).
• Polluzione atmosferica (radiazioni, smog…)
• La letteratura attuale non dimostra che la
terapia con Imatinib aumenta il rischio di
secondi tumori

17. Messaggi da portare a casa
• La LMC è “per se” un fattore predisponente a
secondi tumori (instabilità genetica?!).
• La lunga sopravvivenza (aging) ottenuta con gli
TKIs espone all’insorgenza di secondi tumori.
• Necessità di un’accurata registrazione dei
secondi tumori (età, fattori predisponenti,durata
LMC)
• PREVENZIONE accurata e regolare: non
dimentichiamo che noi siamo medici e non solo
esperti di LMC!

18. GRAZIE
• Grazie ai pazienti che affidano alle nostre
mani non solo la loro malattia ma anche le
loro vite vissute.
• Grazie a chi sostiene in modo trasparente
la ricerca.
• Grazie alle Associazioni, alle Onlus
• E grazie per le domande che vorrete fare!