Pt no / CML occurring as primary/ secondary / Age at diagnosis of CML / Sex / CML diagnosis month/years / Treatment before imatinib / Duration of treatment before imatinib
(months) / CML status at diagnosis / Dose of imatinib / Best imatinib response / Duration of imatinib (m) / Overall duration of CML (m) / Status of cml at last followup
1 / Primary / 47 / M / 12/1992 / Hydroxyurea
IFN Alpha / 48
120 / CP / 400mg / MMR- MR4.5 / 156 / 276 / CMR
2 / Primary / 25 / F / 4/2004 / Hydroxyurea / 3 / CP / 400mg X 12m
800 mg X 7m / CCyR / 21 / 25 / Died due to BC
3 / Primary / 58 / F / 5/2007 / Hydroxyurea / 2 / CP / 400 mg / MMR – MR3 / 72 / 74 / LFU Since 9.5.13
4 / Primary / 62 / F / 1/2008 / Hydroxyurea / 2 / AP / 600 mg X 31m
800 mg X 27m / CCyR / 58 / 60 / Died due to BC
5 / Primary / 65 / M / 11/2008 / Hydroxyurea / 7 / CP / 400mg / CCyR / 70 / 77 / CCyR
6 / Primary / 50 / F / 1/2011 / Hydroxyurea / 5 / CP / 400 mg / CCyR / 43 / 48 / CCyR
7 / Primary / 45 / F / 4/2011 / Hydroxyurea / 2 / AP / 600mg / MMR- MR4 / 46 / 48 / CMR
8 / Primary / 25 / F / 4/2011 / Hydroxyurea / 3 / CP / 400mg / MMR- MR4 / 43 / 46 / CMR
9 / Synchronous / 62 / M / 11/2007 / Hydroxyurea / 0.5 / CP / 400 mg / CCyR / 87.5 / 88 / CCyR
10 / Synchronous / 32 / F / 4/2014 / Hydroxyurea / 0.75 / CP / 400mg / MMR-MR4 / 12 / 12 / CMR
11 / Synchronous / 66 / M / 8/2014 / No Drugs / Not applicable / CP / 400 mg / MMR- MR4.5 / 8 / 8 / CMR
12 / Secondary / 44 / F / 10/2008 / Hydroxyurea / 1 / CP / 400 mg / MMR-MR4.5 / 76 / 77 / CMR
13 / Secondary / 37 / M / 4/2011 / Hydroxyurea / 0.5 / CP / 400 mg X 24m
600mg X 22m / CCyR / 45.5 / 46 / CCyR
14 / Secondary / 58 / F / 6/2014 / Hydroxyurea / 1 / CP / 400 mg X 7m
600mg x 3m / CHR / 9 / 10 / CHR
15 / Secondary / 51 / F / 11/2014 / Hydroxyurea / 0.5 / CP / 400 mg / CHR / 3.5 / 4 / CHR
M- Male; F- Female; CP – Chronic phase, AP – Accelerated phase, CCyR – Complete cytogenetic remission, CHR – complete haematological remission, MMR – major molecular remission (molecular remission status defined based on ELN criteria), LFU – Lost to follow up, BC – blast crisis
Supplement Table 2: Synchronous Malignancies With CMLAuthor / Publication type / year / Age / sex / CML phase / Second malignancy
Bekkenk et al(1) / Case report / 2003 / 70/M / Chronic / EBV positive cutaneous B cell lymphoma
Bahl et al (2) / Case report / 2010 / 45/M / Chronic / Carcinoma Breast
Abhijeet et al (3) / Case report / 2014 / 52 /M / Chronic / Carcinoma Penis
Supplement Table 3: Metachronous Malignancies In CML Patients: Pre-Imatinib Era
Publication type / Author / Year of publication / Number of CML cases / Number of SM / Interferon duration
Case report / Montefusco et al(4) / 1993 / - / T-ALCL / NA
Case series / Ichinohasama et al (5) / 1999 / - / 2 (DLBCL, ALCL) / NA
Prospective / Kolb et al(6) / 1999 / 1036 ( post BMT) / 53 / NA
Retrospective / Bhatia et al(7) / 2001 / 392 / 6 (All either cervical/oral) / NA
RCT / Hehlmann et al(8) / 2003 / 376 / 8 / NA
Correspondence / Roy et al(9) / 2005 / 189 / 6 (1 Bladder, 4 Prostate ) / 5-96 months
Retrospective / Ishibe et al(10) / 2006 / 8005 / 334 / NA
Retrospective / Rizzo et al(11) / 2009 / 7594 / 189 / NA
Population based / Rebora et al(12) / 2010 / 2735 / 145 / NA
Retrospective / Majhail et al (13) / 2011 / 2576 / 44 / NA
SM – Secondary malignancy; CML – chronic myeloid leukaemia;
Supplement Table 4: Metachronous Malignancies In CML Patients: Post-Imatinib EraPublication Type / Author / Published (year) / Total CML (n) / Total SM (n) / Median follow up (months) / Type of SM / Median Imatinib (months)
Case report / Chee et al(14) / 2003 / - / 1 / NA / tMDS ( post-transplant) / 9
Case report / Mozziconacci et al(15) / 2003 / - / 1 / NA / tMDS ( post-transplant) / 19
Case series / Baskaynak et al (16) / 2003 / - / 2 / 17/164* / CutaneousSquamousCell Carcinoma / 17/36
Case report / Rodler et al(17) / 2004 / 1 / 1 / Mantle Cell Lymphoma / 36
Correspondence / Roy et al(9) / 2005 / 189 / 6 / 60 / 31.2
Epidemiological / Pilot et al (18) / 2005 / 9518 / 110 / NA / 16-Prostate, 2-Bladder, 3-Kidney / NA
Retrospective / Voglova et al (19) / 2010 / 1038 / 35 / 51* / NA / 32
Case series / Budrukkar et al(20) / 2011 / - / 7 / 14^ / All head and neck cancers / NA
Retrospective / Verma et al(21) / 2011 / 1445 / 56 / 107* / NA / 39
Case series / Duman et al (22) / 2012 / - / 7 / 2-NHL, 1-Colon, 1-Stomach, 1- Lung SCC, 1-Dermatofibroma, 1-Thyroid Papillary / NA
Retrospective / Yoshimoto et al(23) / 2014 / 52 / 6 / 132 / Stomach, liver, MM, Brain, Colon, lung, vulva / 132
Retrospective / Binay et al (24) / 2014 / 8551 / 473 / 13
Case series / Helbig et al(25) / 2015 / 221 / 8 / NA / 1-Endometrium, 1-Testis, 1-Lung, 1-Skin, 1-Colon, 1-Bladder, 1-Breast, 1-Prostate / 61
NA – Not available
Supplement Table 5 : Postulations of how imatinib can cause secondary malignancies- Decreasing NK cell activity following imatinib therapy making individuals prone to development of other malignancies (3).
- Concurrent exposure to tobacco and alcohol increases the likelihood of developing secondary head and neck malignancies (20).
- Acquiring additional cytogenetic abnormalities in patients on imatinib with CML in complete remission suggests role in carcinogenesis (26).
- Imatinib might inhibit other tyrosine kinases which are negative regulators of various cycle processes involved in stringent regulation of cell proliferation (27).
- Inhibitory impact of TKI (Imatinib) on dendritic cell and T cell stimulation (28, 29)
- Inhibition of C-ablkinases which have a role in potentiating apoptosis of DNA damaged cells (25).
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