Supplement Table 1: Disease characteristics of CML in patient with dual malignancies
Pt no
CML occurring as
primary/ secondary
1
Primary
2
Primary
3
Primary
4
Primary
5
Primary
6
Primary
7
Primary
8
Primary
9
Synchronous
10
Synchronous
11
Synchronous
12
Secondary
13
Secondary
14
Secondary
15
Secondary
Age at diagnosis
of CML
47
25
58
62
65
50
45
25
62
32
66
44
37
58
51
Sex
CML diagnosis
month/years
M
12/1992
Hydroxyurea
Duration of
treatment before
imatinib
(months)
48
IFN Alpha
120
Treatment before
imatinib
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
CP
400mg
MMRMR4.5
156
276
CMR
F
4/2004
Hydroxyurea
3
CP
400mg X 12m
800 mg X 7m
CCyR
21
25
Died due to BC
F
5/2007
Hydroxyurea
2
CP
400 mg
MMR –
MR3
72
74
LFU Since 9.5.13
F
1/2008
Hydroxyurea
2
AP
600 mg X 31m
800 mg X 27m
CCyR
58
60
Died due to BC
M
11/2008
Hydroxyurea
7
CP
400mg
CCyR
70
77
CCyR
F
1/2011
Hydroxyurea
5
CP
400 mg
CCyR
43
48
CCyR
F
4/2011
Hydroxyurea
2
AP
600mg
MMR- MR4
46
48
CMR
F
4/2011
Hydroxyurea
3
CP
400mg
MMR- MR4
43
46
CMR
M
11/2007
Hydroxyurea
0.5
CP
400 mg
CCyR
87.5
88
CCyR
F
4/2014
Hydroxyurea
0.75
CP
400mg
MMR-MR4
12
12
CMR
M
8/2014
No Drugs
Not applicable
CP
400 mg
MMRMR4.5
8
8
CMR
F
10/2008
Hydroxyurea
1
CP
400 mg
MMR-MR4.5
76
77
CMR
M
4/2011
Hydroxyurea
0.5
CP
CCyR
45.5
46
CCyR
F
6/2014
Hydroxyurea
1
CP
CHR
9
10
CHR
F
11/2014
Hydroxyurea
0.5
CP
CHR
3.5
4
CHR
400 mg X 24m
600mg X 22m
400 mg X 7m
600mg x 3m
400 mg
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 CML
Author
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 Era
Publication 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*
Cutaneous Squamous Cell 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
Stomach, liver, MM, Brain, Colon, lung, vulva
132
Retrospective
Binay et al (24)
2014
8551
473
Case series
Helbig et al(25)
2015
221
8
132
13
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-abl kinases which have a role in potentiating apoptosis of DNA damaged cells (25).
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