Modern Pathologyhttps://doi.org/10.1038/s41379-018-0014-x
ARTICLE
Secondary Philadelphia chromosome acquired during therapy ofacute leukemia and myelodysplastic syndrome
Habibe Kurt1 ● Lan Zheng1● Hagop M. Kantarjian2
● Guilin Tang1● Farhad Ravandi-Kashani2 ●
Guillermo Garcia-Manero2● Zimu Gong1
● Hesham M. Amin1● Sergej N. Konoplev1 ● Mark J. Routbort1 ● Xin Han3
●
Wei Wang1● L. Jeffery Medeiros1 ● Shimin Hu 1
Received: 3 October 2017 / Revised: 29 November 2017 / Accepted: 3 December 2017© United States & Canadian Academy of Pathology 2018
AbstractThe Philadelphia chromosome resulting from t(9;22)(q34;q11.2) or its variants is a defining event in chronic myeloidleukemia. It is also observed in several types of de novo acute leukemia, commonly in B lymphoblastic leukemia, and rarelyin acute myeloid leukemia, acute leukemia of ambiguous lineage, and T lymphoblastic leukemia. Acquisition of thePhiladelphia chromosome during therapy of acute leukemia and myelodysplastic syndrome is rare. We reported 19 patients,including 11 men and 8 women with a median age of 53 years at initial diagnosis. The diagnoses at initial presentation wereacute myeloid leukemia (n= 11), myelodysplastic syndrome (n= 5), B lymphoblastic leukemia (n= 2), and Tlymphoblastic leukemia (n= 1); no cases carried the Philadelphia chromosome. The Philadelphia chromosome wasdetected subsequently at relapse, or at refractory stage of acute leukemia or myelodysplastic syndrome. Of 14 patientsevaluated for the BCR-ABL1 transcript subtype, 12 had the e1a2 transcript. In 11 of 14 patients, the diseases before and afteremergence of the Philadelphia chromosome were clonally related by karyotype or shared gene mutations. Of 15 patients withtreatment information available, 7 received chemotherapy alone, 5 received chemotherapy plus tyrosine kinase inhibitors, 2received tyrosine kinase inhibitors only, and 1 patient was not treated. Twelve patients had follow-up after acquisition of thePhiladelphia chromosome; all had persistent/refractory acute leukemia. Thirteen of 15 patients died a median of 3 monthsafter the emergence of the Philadelphia chromosome. In summary, secondary Philadelphia chromosome acquired duringtherapy is rare, and is associated with the e1a2 transcript subtype, terminal disease stage, and poor outcome.
Introduction
The Philadelphia chromosome resulting from t(9;22)(q34;q11.2) or its variants is the hallmark of chronic myeloidleukemia [1]. It is also observed in several types of de novo
acute leukemia, commonly in B lymphoblastic leukemia[2], and rarely in acute myeloid leukemia [3–5], acuteleukemia of ambiguous lineage [6, 7], and T lymphoblasticleukemia [8, 9]. Different break point sites within the BCRgene result in different BCR-ABL1 fusion transcript sub-types that may affect the disease phenotype. The typicalb2a2/b3a2 fusion transcripts, which encode P210, are foundin over 95% of patients with chronic myeloid leukemia. Thee1a2 fusion transcript, which encodes P190, is seen in mostpatients with Philadelphia chromosome-positive B lym-phoblastic leukemia, and is associated with monocytosis inchronic myeloid leukemia [10]. Patients with chronicmyeloid leukemia and the e1a2 transcript have a higher riskof blastic transformation, poor treatment response, andunfavorable survival compared with patients with the typi-cal b2a2/b3a2 transcripts [11]. Cases of chronic myeloidleukemia that carry the rare e19a2 transcript, which encodesP230, often show prominent neutrophilic maturation orthrombocytosis [12, 13].
* Shimin [email protected]
1 Department of Hematopathology, The University of Texas MDAnderson Cancer Center, Houston, TX, USA
2 Department of Leukemia, The University of Texas MD AndersonCancer Center, Houston, TX, USA
3 Department of Laboratory Medicine, The University of Texas MDAnderson Cancer Center, Houston, TX, USA
Electronic supplementary material The online version of this article(https://doi.org/10.1038/s41379-018-0014-x) contains supplementarymaterial, which is available to authorized users.
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All subtypes of BCR-ABL1 transcripts encode fusion pro-teins with constitutive tyrosine kinase activity that is essentialfor inducing leukemia via increasing tumor cell proliferationand growth, reducing adherence to bone marrow stroma [1],and promoting angiogenesis, metastasis, and a defectiveapoptotic response [14]. An understanding of the abnormalsignaling pathway has led to the development of smallmolecule tyrosine kinase inhibitors targeting BCR-ABL1.This targeted therapy has dramatically improved the outcomeof patients with chronic myeloid leukemia [15], and to a lesserextent, Philadelphia chromosome-positive B lymphoblasticleukemia [16–18]. Improved survival in patients with de novoPhiladelphia chromosome-positive acute myeloid leukemiahas also been reported anecdotally [19].
Myeloid and lymphoid neoplasms in which the Phila-delphia chromosome appears as a primary change at diseaseonset are well-established entities, and have been exten-sively studied. However, secondary Philadelphia chromo-some acquired during therapy of myeloid or lymphoidneoplasms is extremely rare, and only sporadically descri-bed in the form of single-case reports in the literature [20–53]. The biological and clinical features of these cases havenot been systematically studied, and the prognostic sig-nificance of secondary Philadelphia chromosome is poorlyunderstood. Here, we reported 19 patients who acquired thePhiladelphia chromosome during therapy of myeloid orlymphoid neoplasms and provided an overview of casesreported in the literature.
Methods
Patient selection
Patients with myeloid or lymphoid neoplasms diagnosed inour institution from 1998 through 2016 were reviewed forthe presence of the Philadelphia chromosome acquiredduring therapy. Patients with following Philadelphiachromosome-positive diseases were not included: chronicmyeloid leukemia, de novo B- or T lymphoblastic leukemia,de novo acute myeloid leukemia, and de novo acute leu-kemia of ambiguous lineage. Patient demographics, clinicalhistories, including treatment and follow-up information,and laboratory data were obtained by electronic chartreview. This study was approved by the InstitutionalReview Board at the University of Texas MD AndersonCancer Center and was conducted in accordance with theDeclaration of Helsinki.
Flow cytometric immunophenotyping
Flow cytometric immunophenotypic analysis was per-formed on bone marrow aspirates using standard multicolor
analysis, which evolved substantially during the studyinterval. The following antibodies were used in variouscombinations: CD2, CD3 (surface and cytoplasmic), CD4,CD5, CD7, CD13, CD14, CD15, CD19, CD20, CD22,CD25, CD33, CD34, CD36, CD38, CD41, CD45, CD56,CD64, CD117, CD123, HLA-DR, MPO, and TDT (Becton-Dickinson, Biosciences, San Jose, CA, USA). Data wereanalyzed using FCS Express (De novo Software, Glendale,CA).
Cytogenetic studies
Conventional chromosomal analysis was performed on G-banded metaphase cells prepared from unstimulated bonemarrow aspirate cultures (24 and 48 h) using standard GTGbanding. At least 20 metaphases were analyzed. Resultswere reported using the 2013 International System forHuman Cytogenetic Nomenclature [54]. Fluorescencein situ hybridization (FISH) analysis for BCR-ABL1 fusionwas performed on freshly harvested aspirate smears orcultured cells with LSI-BCR-ABL1 ES fusion probes(Abbott Molecular/Vysis, Des Plaines, IL) using previouslydescribed methods [55]. At least 200 interphase nuclei wereanalyzed.
Detection of BCR-ABL1 transcripts
Reverse transcription-quantitative polymerase chain reac-tion (PCR) for detection of BCR-ABL1 transcripts [e1a2,e13a2 (b2a2), and e14a2 (b3a2)] was performed using RNAextracted from bone marrow or peripheral blood sampleswith sensitivities of 1 in 10,000 and 1 in 100,000, respec-tively, according to methods described previously [56, 57].Quantitative results were expressed as the percent ratio ofBCR-ABL1 to ABL1. The sizes of fusion transcripts weredetermined by capillary electrophoresis.
Mutation analysis
Mutation analysis was performed using DNA extractedfrom bone marrow aspirate samples in a subset of patientsusing the following techniques. Next-generation sequen-cing-based analysis was performed to detect somaticmutations in the entire coding sequences of 28 genes(ABL1, EGFR, GATA2, IKZF2, MDM2, NOTCH1, RUNX1,ASXL1, EXH2, HRAS, JAK2, MLL, NPM1, TET2, BRAF,FLT3, IDH1, KIT, MPL, NRAS, TP53, DNMT3A, GATA1,IDH2, KRAS, MYD88, PTPN11, WT1) or in hotspots of 53genes (ABL1, CSF1R, FGFR1, HRAS, KRAS, PIK3CA,SRC, AKT1, CTNNB1, FGFR2, IDH1,MET, PTEN, STK11,ALK, DNMT3A, FGFR3, IDH2, MLH1, PTPN11, TP53,APC, EGFR, FLT3, JAK2, MPL, RB1, VHL,ATM, ERBB2,GNA11, JAK3, NOTCH1, RET, XPO1,BRAF, ERBB4,
H. Kurt et al.
Table1
Clin
ical
characteristicsof
patientswith
second
aryPhiladelphiachromosom
e
No.
Initial
Dx
Sex/age
(years)
Dxat
Phem
ergence
Interval
toPh
(mon
ths)
BCR-A
BL1
transcript
Txandrespon
sebefore
Ph
Txandrespon
seafterPh
OSfrom
Ph
(mon
ths)
Patient
status
Disease
status
1AML
M/22
AML,1strelapse
9e1a2
Chemo
Chemo
1Dead
Refractory
CR
Norespon
se
2AML
F/31
AML,3rdrelapse
17e1a2
Chemo,
HSCT
Chemo,
sorafenib
3Dead
Refractory
CR
Norespon
se
3AML
F/26
AML,3rdrelapse
26b3
a2andb2
a2Chemo,
HSCT
Chemo,
dasatin
ib,
ponatin
ib4
Dead
Refractory
CR
Norespon
se
4AML
F/57
AML,3rdrelapse
26e1a2
Chemo,
HSCT
Chemo,
dasatin
ib4
Dead
Refractory
CR
Norespon
se
5AML
F/66
AML,1strelapse
9NA
Chemo,
HSCT
Chemo
1Dead
Refractory
CR
Norespon
se
6AML
M/63
AML,refractory
9b2
a2Chemo
Chemo,
dasatin
ibNA
Lostin
F/U
NA
Norespon
seInitial
respon
se
7AML
M/65
AML,2n
drelapse
15e1a2
Chemo
Chemo,
dasatin
ib9
Dead
Refractory
CR
Norespon
se
8AML
M/52
AML,refractory
6NA
Chemo
Chemo
4Dead
Refractory
Norespon
seNorespon
se
9AML
M/28
AML,1strelapseand
prog
ression
18NA
Chemo
Chemo
NA
Lostin
F/U
NA
Norespon
seNA
10AML
M/42
AML,3rdrelapseand
prog
ression
14e1a2
Chemo,
HSCT
Chemo
5Dead
Refractory
Norespon
seNorespon
se
11AML
M/39
AML,refractory
11e1a2
Chemo
Chemo
8Aliv
eRefractory
Norespon
seNorespon
se
12MDS
F/48
sAML,2n
drelapse
14e1a2
Chemo
Chemo
2Dead
Refractory
CR
Norespon
se
13MDS
F/58
sAML,prog
ression
72e1a2
Chemo
NA
NA
Lostin
F/U
NA
Progression
14MDS
M/78
sAML,1strelapse,
then
persistent
MDS
20NA
Chemo
NA
NA
Lostin
F/U
NA
CR
15MDS
M/69
sAML,refractory
38NA
Chemo
Notreatm
ent
1Dead
Refractory
Refractory
Secondary Philadelphia chromosome acquired during therapy
GNAQ, KDR, NPM1, SMAD4, CDH1, EZH2, GNAS, KIT,NRAS, SMARCB1, CDKN2A, FBXW7, HNF1A, KLHL6,PDGFRA, SMO1). The next-generation sequencing assayswere performed using the Illumina MiSeq sequencer (Illu-mina, San Diego, CA) with a sensitivity of 5% as describedpreviously [58, 59]. FLT3-ITD, FLT3 D835, and NPM1(exon 12, codons 956–971) mutations were assessed byPCR followed by capillary electrophoresis on a geneticanalyzer (Prism ABI 3130, Applied Biosystems, FosterCity, CA) as described previously [60]. NRAS (codons 12,13, 61), KRAS (codons 12, 13, 61), IDH1 (exon 4, codons87–138), IDH2 (exon 4), KIT (exons 8 and 17), and JAK2(codon 617) mutations were assessed by PCR followed bySanger sequencing with a sensitivity of 20% as describedpreviously [58, 61]. PCR-based cDNA sequencing of BCR-ABL1 was performed to detect mutations in codons221–500 of the ABL1 kinase domain by using pyr-osequencing PSQ96 HS System (Biotage AB, Uppsala,Sweden) per the manufacturer’s instructions. The lowerlimit of detection of the assay is 5% mutation-bearing cellsin the test samples. PCR-based microsatellite polymorphismanalysis was performed by using GENESCAN on the pre-transplant, donor, and post-transplant samples.
Results
Timing of emergence of secondary Philadelphiachromosome
A total of 19 patients were identified to have secondary t(9;22)(q34;q11.2)/BCR-ABL1 detected by chromosomalbanding analysis during therapy of acute leukemia ormyelodysplastic syndrome. The diagnoses at initial pre-sentation were acute myeloid leukemia (n= 11), myelo-dysplastic syndrome (n= 5), B lymphoblastic leukemia (n= 2), or T lymphoblastic leukemia (n= 1) (Table 1). Novariant BCR-ABL1 rearrangements were identified. Therewere 11 men and 8 women with a median age of 53 years(range, 18–78 years) at initial diagnosis, and 56 years(range, 19–79 years) at time of emergence of secondaryPhiladelphia chromosome.
Of the 11 patients with an initial diagnosis of acutemyeloid leukemia, 6 patients acquired secondary Philadel-phia chromosome at time of first to 3rd relapse, 2 acquiredsecondary Philadelphia chromosome during progression ofacute myeloid leukemia after 1–3 relapses, and 3 acquiredsecondary Philadelphia chromosome during treatment ofrefractory disease (patients never achieved remission beforethe emergence of secondary Philadelphia chromosome)(Table 1). Of the five patients with an initial diagnosis ofmyelodysplastic syndrome, all developed secondary acutemyeloid leukemia, and acquired the PhiladelphiaTa
ble1(con
tinued)
No.
Initial
Dx
Sex/age
(years)
Dxat
Phem
ergence
Interval
toPh
(mon
ths)
BCR-A
BL1
transcript
Txandrespon
sebefore
Ph
Txandrespon
seafterPh
OSfrom
Ph
(mon
ths)
Patient
status
Disease
status
16MDS
M/62
sAML,1strelapseand
Refractory
42e1a2
Chemo
Imatinib,nilotin
ib3
Dead
Refractory
Refractory
Norespon
se
17B-A
LL
M/64
B-A
LL,1strelapse
26e1a2
ChemoCR
Chemo,
bosutin
ib,
HSCTCR
6Aliv
eCR
18B-A
LL
F/53
B-A
LL,1strelapseand
refractory
t-AML
40e1a2
Chemo
Imatinib
with
CR
and
refractory
t-AML
4Dead
Refractoryt-
AML
Norespon
se
19T-A
LL
F/18
2ndrelapseandrefractory
19e1a2
Chemo
Chemo
1Dead
Refractory
Refractory
Norespon
se
Dxdiagno
sis,Txtreatm
ent,PhPhiladelphiachromosom
e,Interval
intervaltim
efrom
initialdiagno
sisto
theem
ergenceof
Ph,
OSov
erallsurvival,AMLacutemyeloid
leuk
emia,sAMLsecond
ary
AML,M
DSmyelody
splasticsynd
rome,B-ALLBlymph
oblasticleuk
emia,T
-ALLTlymph
oblasticleuk
emia,t-AMLtherapy-relatedAML,M
male,Ffemale,Chemochem
otherapy
,CRcomplete
remission
,HSC
Thematop
oietic
stem
celltransplantation,
F/U
follo
w-up,
NAno
tavailable
H. Kurt et al.
chromosome when secondary acute myeloid leukemiadeveloped (n= 1), relapsed (n= 1), relapsed and becamerefractory to treatment (n= 2), or after relapse with per-sistent myelodysplastic syndrome (1% blasts in bone mar-row) (n= 1). The two patients with an initial diagnosis of Blymphoblastic leukemia acquired the Philadelphia chromo-some at relapse or at a refractory stage after relapse,respectively. In the patient with T lymphoblastic leukemia,the Philadelphia chromosome was acquired during treat-ment of refractory disease after two relapses. Among thepatients with an initial diagnosis of acute myeloid leukemiaor acute lymphoblastic leukemia, the median interval fromthe initial diagnosis of acute leukemia to the acquisition ofsecondary Philadelphia chromosome was 16 months (range,6–40 months). Among the patients with an initial diagnosisof myelodysplastic syndrome, the median interval from theinitial diagnosis of myelodysplastic syndrome to the
emergence of secondary Philadelphia chromosome was38 months (range, 14–72 months), and the median intervalfrom the development of secondary acute myeloid leukemiato the emergence of secondary Philadelphia chromosomewas 9 months (range, 0–37 months).
Complete blood count data and bone marrowmorphology after acquisition of Philadelphiachromosome
At emergence of secondary Philadelphia chromosome, 18patients had anemia (range, 8.4–11.5 g/dl), 16 had throm-bocytopenia (range, 8–104× 103/μ), and 8 had leukopenia(range, 1.0–3.8× 103/μl) (Supplemental Table 1). Circu-lating blasts (range, 2–96%) were seen in 15 patients. Ineight patients who had leukocytosis (range, 13.9–89.2×103/μl), blasts were the predominant cell population in five
Fig. 1 Morphology of blastsbefore and after emergence ofsecondary BCR-ABL1. a, b Blastmorphology of patient withacute myeloid leukemia (#8)before (a) and after (b) theemergence of secondary BCR-ABL1. c, d Blast morphology ofpatient with myelodysplasticsyndrome (#16) before (c) andafter (d) the emergence ofsecondary BCR-ABL1. e, f Blastmorphology of patient with Tlymphoblastic leukemia (#19)before (e) and after (f) theemergence of secondary BCR-ABL1. Original magnification:x1000
Secondary Philadelphia chromosome acquired during therapy
patients. Six patients had absolute monocytosis at the timeof emergence of secondary Philadelphia chromosome, andfour of them had monocytosis before acquisition of thePhiladelphia chromosome. Absolute eosinophilia, basophi-lia, and left-shifted granulocytes, features of chronic mye-loid leukemia, were observed in only one patient (#13).
Bone marrow smears both before and after detection ofsecondary Philadelphia chromosome were available forretrospective review in nine patients. There was no changein the morphology of blasts before versus after emergenceof secondary Philadelphia chromosome (Fig. 1), except inpatient #1 whose blasts appeared more monoblastic atdetection of secondary Philadelphia chromosome [62]. Noimmunophenotypic shift in the blasts was detected by flowcytometric analysis in 14 patients with available data (#1, 2,4, 5, 6, 7, 9, 11, 12, 13, 16, 17, 18, and 19). Given theevolving nature of flow cytometry methods over the courseof this study, however, blasts were evaluated with only alimited number of markers in early cases.
Clonal relatedness between diseases before and atemergence of secondary Philadelphia chromosome
Detailed cytogenetic and molecular findings at initialdiagnosis, and before and after the emergence of secondaryPhiladelphia chromosome are provided in Tables 2 and 3.
Karyotypes at initial diagnosis were available in 16patients (Table 2). Seven patients had a normal karyotypeand nine had an abnormal karyotype. In seven of ninepatients with an abnormal karyotype at initial diagnosis, theinitial chromosomal alterations were present in the sec-ondary Philadelphia chromosome-positive clones, thus thediseases before and at the emergence of the Philadelphiachromosome were clonally related, and the emergence ofsecondary Philadelphia chromosome may represent clonalevolution.
In five of seven patients with a normal karyotype, testsfor molecular mutations with a limited panel were per-formed in bone marrow samples obtained before and at timeof emergence of secondary Philadelphia chromosome.Common molecular mutations were detected before and atemergence of secondary Philadelphia chromosome in fourpatients (Table 3). FLT3-ITD mutation in patients #2 and10, NPM1 mutation in patient #4, and NRAS mutation inpatient #6. Of note, the post-transplant microsatellite poly-morphism pattern showed a mixed chimera in three patientstested (#2, 4, and 5), supporting the recipient origin ofrelapsed disease.
BCR-ABL1 transcript subtype and ABL1 mutation
FISH analyses were performed in 16 patients, and BCR-ABL1 rearrangement was confirmed positive in all. In 14
patients tested by reverse transcription-quantitative PCR forBCR-ABL1 transcript subtype, the e1a2 fusion transcripts(P190) were identified in 12 patients (86%). In the other twopatients (#3 and 6), b2a2 or simultaneous b2a2 and b3a3transcripts were identified, respectively. Of five patientsanalyzed for ABL1 kinase domain mutations (#2, 3, 7, 16,and 17), only one (#7) showed a mutation (p.G254E)(Table 3).
Evolution of secondary Philadelphia chromosome-positive clones during therapy
Before the emergence of secondary Philadelphia chromo-some detectable by chromosomal banding analysis, BCR-ABL1 rearrangement or fusion transcripts were tested ineight patients by either FISH (n= 3) or reversetranscription-quantitative PCR (n= 4) or both (n= 1). Alow level of BCR-ABL1 fusion transcripts was detected inthree patients either at initial presentation (#1, 0.11%; #11,0.01%) or later during therapy (#18, 0.70%) by reversetranscription-quantitative PCR, but not by FISH. The BCR-ABL1 transcript subtype was of e1a2 in all three patients.The median time from the detection of low level of BCR-ABL1 by reverse transcription-quantitative PCR to theemergence of secondary Philadelphia chromosome detectedby karyotyping was 9 months (range, 5–11 months).
After the emergence of secondary Philadelphia chromo-some detected by karyotyping, the Philadelphiachromosome-positive subclones were the major one in 11patients, simultaneously with the emergence of secondaryPhiladelphia chromosome in eight patients (#1, 6, 7, 9, 13,16, 17, and 19) and shortly after the emergence of sec-ondary Philadelphia chromosome in three patients (#4, 12,and 18). The Philadelphia chromosome-positive subcloneswere a minor clone in the remaining eight patients. Twelvepatients had follow-up information on the evolution ofPhiladelphia chromosome-positive subclones after initialdetection. The Philadelphia chromosome-positive subcloneswere persistent by FISH analysis in six patients (#2, 6, 8,11, 12, and 16) despite chemotherapy with or without tyr-osine kinase inhibitors. In the remaining six patients (#3, 4,7, 10, 17, and 18), the Philadelphia chromosome-positivesubclones were undetectable by FISH analysis, includingthree patients (#4, 10, and 17) with undetectable BCR-ABL1transcripts by reverse transcription-quantitative PCR. Ofthose six patients with undetectable Philadelphiachromosome-positive subclones, five were treated withtyrosine kinase inhibitors and one received conventionalchemotherapy. Interestingly, all 12 patients had persistent orrefractory acute myeloid leukemia or acute lymphoblasticleukemia regardless of the presence or absence of the Phi-ladelphia chromosome-positive subclones, including onepatient (#18) with refractory therapy-related acute myeloid
H. Kurt et al.
Table2
Secon
dary
BCR-ABL1detected
bykaryotyp
ing,
FISH,andmolecular
analyses
No.
Atinitial
Dxa
Immediately
before
emergenceof
Ph
Atandafterem
ergenceof
Ph
146
,XY,t(3;13
)(q2
7;q1
4)[1]/45
,XY,t(3;13
)(q2
7;q1
4),−
7[19]
46,XY
[20]
Initial:45
,XY,t(3;13
)(q2
7;q1
4),-7[3]/45
,XY,t(3;13
)(q2
7;q1
4),-7,t(9;22
)(q3
4;q1
1.2)
[14]/46,XY
[3]
FISH(−
);Q-PCR(+
):0.1%
FISH(+
):50
%
246
,XX
[20];
46,XX
[1]/46
,XY
[19]
b1.
Initial:46
,XX,t(9;22
)(q3
4;q1
1.2)
[7]/46
,XX
[2]/46
,XY
[11];FISH(+
):9%
Q-PCR(−
)at
1strelapse
2.RefractoryAML,6wkafterPh,
before
sorafenib:
FISH(+
):68
%;Q-PCR
(+):55
.33%
3NA
46,XX,t(2;17
)(p2
1;p1
1.2),t(14
;17)(q24
;q25
)[16]/46,XX
[4]b
1.Initial:46
,XX,del(2)(p2
3),add
(14)(q11
.2),−17
,+mar
[8]/46
,idem
,t(9;22
)(q34
;q11
.2)[2]/46
,idem
[cp4
]/46
,XX,del(1)(q4
2),del(11)(q13
q23)
[4]/46
,XX
[2];FISH(+
):6.5%
;Q-PCR(+
),9.28
%
2.PersistentAML,11
wkafterPh,
7wkafterpo
natin
ib;FISH(−
)
446
,XX
[20]
46,XY
[20]
b1.
Initial:46
,XX,t(9;22
)(q3
4.1;q1
1.2)
[5]//46,XY
[15]
FISH(+
):6.5%
FISH(−
)at
2ndrelapse
2.PersistentAML,4wkafterPh:
Q-PCR(+
):80
.92%
3.PersistentAML,10
wkafterPh/7wkafterdasatin
ib:Q-PCR(−
)
548
,XX,+
6,+8[18]/46,XX
[2]
46,XX
[19]
bInitial:46
,XX,t(15
;17)(q15
;q11
)[8]/46
,XX,t(2;7)(p21
;q36
),t(9;22
)(q3
4;q1
1.2),add
(12)(p11
.2),t(15
;17)(q15
;q11
)[4]/46
,X,t(X;15;17
)(p2
2;q1
5;q1
1)[8]
646
,XY
[20];Q-PCR(-)2mon
thslater
46,XY
[20]
1.Initial:46
,XY,t(9;22
)(q3
4;q1
1.2)
[15]/46,XY
[5];FISH(+
):39
%;Q-PCR
(+)
2.PersistentAML,2wkafterPh,
before
dasatin
ib:FISH(+
):48
%
746
,XY,in
v(16
)(p1
3q22
)[20]
46,XY,?del(16
)(q2
2)[3]/46
,XY
[17]
1.Initial:46
,XY,in
v(16
)(p1
3q22
)[2]/48
,idem
,t(9;22
)(q3
4;q1
1.2),+
13,+
22[16]/47,XY,in
v(16
)(p1
3q22
),+13
[1]/48
,XY,in
v(16
)(p1
3q22
),+13
,+22
[1]
FISH(+
):4.5%
Q-PCR(+
):8.81
%
2.PersistentAML,8wkafterPh,
4wkafterdasatin
ib:Q-PCR(+
):<0.01
%
845
,XY,in
v(3)(q21
q26.2),−
7[10]/46,XY
[10]
45,XY,in
v(3)(q21
q26.2),−
7[20];FISH(−
)Initial:45
,XY,in
v(3)(q21
q26.2),−
7[19]/44,XY,in
v(3)(q21
q26.2),−
7,t(9;22
)(q34
;q11
.2),−18
[1];FISH(+
):2.5%
946
,XY
46,XY
[19]
Initial:46
,XY,t(9;22
)(q3
4;q1
1.2)
[14]/46–
47,XY,del(3)(p1
3),t(9;22
)(q3
4;q1
1.2),+
mar[cp4
]/46
,XY
[2]
1046
,XY
46,XY
b1.
Initial:46
,XY,del(20)(q11
.2q1
3.3)
[3]/46
,XY,t(9;22
)(q3
4;q1
1.2)
[1]/46
,XY,t(1;16
)(p3
3;q2
4)[1]/46
,XY
[15];FISH(+
):0.4%
2.PersistentAML,6wkafterPh;
Q-PCR(−
)
1145
,XY,in
v(3)(q21
q26.2),−
7[19]/45,idem
,t(5;12
)(q3
1;p1
3)[1]Q-PCR(+
):0.01
%45
,XY,in
v(3)(q21
q26.2),−
7[19]/45
,idem
,t(11;17
)(p1
1.2;p1
1.2)
[1]
1.Initial:8/10
/201
645
,XY,in
v(3)(q21
q26.2),−
7[14]/45,idem
,t(9;22
)(q3
4;q1
1.2)
[5]/45
,idem
,t(11
;17)(q11
.2;q11
.2)[1]
2.RefractoryAML,6
wkafterPh:
45,XY,in
v(3)(q21
q26.2),−
7[19]/46,idem
,+21
[1];FISH(+
):3%
12NA
45,XX,del(5)(q1
3q33
),inv(6)(p11
.2q2
1),add(7)
(p15
),−13
[10]//4
6,XX
[10]
1.Initial:45
,XX,del(5)(q1
3q33
),inv(6)(p11
.2q2
1),add
(7)(p1
5),−
13[3]/45
,idem
,t(9;22
)(q3
4;q1
1.2)
[6]/45
,idem
,17,mar
[1]/46
,XX
[10];FISH(+
):21
%
Secondary Philadelphia chromosome acquired during therapy
Table2(con
tinued)
No.
Atinitial
Dxa
Immediately
before
emergenceof
Ph
Atandafterem
ergenceof
Ph
2.RefractoryAML,8
wkafterPh,before
dasatin
ib:45,XX,del(5)(q1
3q33
),inv
(6)(p1
1.2q
21),add(7)(p15
),t(9;22
)(q3
4;q2
2.1),−
13[20];FISH(+
):94
%;Q-
PCR(+
):>10
0%13
46,XX,t(1;12
)(p1
3;q1
5)[20]
46,XX,t(1;12
)(p1
3;q1
5)[20]
Initial:46
,XX,t(1;12
)(p1
3;q1
5)?c
[3]/46
,XX,t(1;12
)(p1
3;q1
5)?c,t(9;22
)(q3
4;q1
1.2)
[17]
FISH(+
):66
%;Q-PCR(+
):77
.93%
1447
,XY,+
8NA
Initial:46
,XY,t(9;22
)(q3
4;q1
1.2)
[3]/47
,XY,+
8[7]/46
,XY
[10]
1547
,XY,+
2147
,XY,+
21[12]/46,XY
[8]
Initial:47
,XY,in
v(17
)(q1
1.2q
23),+21
[2]/47
,idem
,t(9;22
)(q3
4;q1
1.2)
[2];
FISH(+
):4.5%
16NA
46,XY,t(3;21
)(p2
1;q2
2)[8]/46
,XY
[12]
1.Initial:46
,XY,t(9;22
)(q3
4;q1
1.2)
[17]/46,XY,der(9)t(9;22)(q34
;q11
.2)inv
(9)(p1
2q32
),der(22
)t(9;22)
[2]
2.RefractoryAML,5wkafterPh,
4wkafterim
atinib:46
,XY,t(9;22
)(q3
4;q1
1.2)
[18]/46
,XY,der(9)t(9;22)(q34
;q11
.2)inv
(9)(p1
2q32
),der(22
)t(9;22)
[1];FISH(+
):92
.5%;Q-PCR(+
):>10
0%
1746
,XY
[20];FISH(−
)46
,XY
[20]
1.Initial:48
,XY,+
5,t(9;22
)(q3
4;q1
1.2),+
10,−
21,+
der(22
)t(9;22)
[3]/49
,XY,+
5,t(9;22
),−21
,+der(22
)t(9;22),+
2mar
[1]/46
,XY
[2];FISH(+
):22
.5%;Q-PCR(+
):61
.55%
;
2.CR,10wkafterPh,9wkafterBosutinib:46
,XY
[20];FISH(-);Q-PCR(-)
1846
,XX
[18]
45,XX,−
7[20];Q-PCR(+
)(relapsed/persistent
B-A
LL,6wkbefore
Ph,
low
quality
RNA)
1.Initial
(63%
blasts):45
,XX,−
7[4]/45
,XX,−
7,del(18
)(q2
1)[8]/46
,XX,del
(1)(p1
3),del(4)(p1
5.2),del(5)(q1
3),−
9,t(9;22
)(q3
4;q1
1.2),−
18,+
2mar
[1]/46
,XX
[2]
2.PersistentB-A
LL,3wkafterPh,
before
imatinib:FISH(+
):65
.5%,Q-
PCR(+
):67
.8%
3.t-AML,14
wkafterPh,
9wkafterim
atinib:46
,XX
[30];FISH(-)
1968
~87[3n
],XXX,+
1,+2,+3×
2,+3q
21,+
4,+5,+5q
13,+
9,+9q
10x2
,+10
,+12
,+12
p11.2,+13
,+14
,−16
,−17
,−18
,+19
,+19
p13.1,+20
,+20
q13.3×
2,+22×2,+6m
ar[5]/46
,XX
[15]
74~8
4<4n>,XXX,add
(X)(p2
1),−
1,del(1)
(p21
p36.1),−
2,add(11
)(q2
3),−
13,−
14,−
15,
−17
,der(18
)t(17;18
)(q1
1.2;q1
1.3)x2
,add
(19)
(p13
.3),−22
,+6~
9mar[cp2
]/46
,XX
[18]
Initial:78
~84<
4n>,XXX,add
(X)(p2
1)x2
,−1,der(1)t(1;9)(p13
;q34
),−2,add(2)
(p12
),−4,−5,−9,add(9)(q22
)x2,−10
,−10
,−11
,add
(11)(q23
),−13
,−15
,−16
,−17
,−17
,der(18)t(17
;18)(q11
.2;q11
.3)x2,
add(19
)(p1
3.3),add
(21)(p11
.2)x2,
der(22
)add
(22)(p11
.2)t(9;22)(q34
;q11
.2),−22
,−22
,+ider(?)(?q10
)t(9;22)
(q34
;q11
.2)x2,+2m
ar[cp1
2]/46,XX
[8];FISH(+
):84
.5%;Q-PCR(+
):68
.41%
PhPhiladelphiachromosom
e,FISH
fluo
rescence
insitu
hybridization,
Q-PCRreversetranscriptionqu
antitativepo
lymerasechainreactio
n,NAno
tavailable,
wkweeks,AMLacutemyeloid
leuk
emia,B-ALLBlymph
oblastic
leuk
emia,t-AMLtherapy-relatedAML,PRpartialrespon
se,CRcompleteremission
a Onlykaryotyp
esat
initial
diagno
sisareprov
ided;FISH
orQ-PCR
may
beperformed
later
b Postbo
nemarrow
transplantation
H. Kurt et al.
leukemia resulting from treatment of B lymphoblastic leu-kemia with secondary Philadelphia chromosome.
Treatment and outcome
Before the emergence of secondary Philadelphia chromo-some, all 19 patients received chemotherapy (Table 1). Inaddition, five patients received allogeneic hematopoieticstem cell transplantation. Only nine patients achievedmorphologic remission or deeper response, and all ninepatients developed relapsed disease.
After the emergence of secondary Philadelphia chromo-some, 15 patients had treatment and follow-up informationavailable; the remaining four patients were transferred toother institutions for treatment and were lost to follow-up(Table 1). Seven patients were treated with chemotherapyonly, five treated with chemotherapy plus tyrosine kinaseinhibitors, two treated with tyrosine kinase inhibitors only,and one not treated due to other comorbid conditions.
Thirteen patients died with refractory disease after a medianfollow-up of 3 months (range, 1–9 months) after theemergence of secondary Philadelphia chromosome. Twopatients were living; one (#11) had an initial diagnosis ofacute myeloid leukemia, and had refractory disease at lastfollow-up 8 months after the emergence of secondary Phi-ladelphia chromosome. The other patient (#17) had aninitial diagnosis of B lymphoblastic leukemia, and receivedchemotherapy combined with tyrosine kinase inhibitors, aswell as subsequent allogeneic hematopoietic stem celltransplantation after the emergence of second Philadelphiachromosome. The patient was free of residual disease at lastfollow-up 6 months after the emergence of secondary Phi-ladelphia chromosome. Another patient (#18) with an initialdiagnosis of B lymphoblastic leukemia achieved remissionwith tyrosine kinase inhibitors after the emergence of sec-ondary Philadelphia chromosome. However, this patientdeveloped therapy-related acute myeloid leukemia and diedshortly thereafter.
Table 3 Mutations detected before and at/after emergence of Philadelphia chromosome
No. Mutations before emergence of Ph Mutations at/after emergence of Ph
1 NRAS(+), KRAS(−) FLT3-ITD(−), FLT3 D835(−) FLT3-ITD(−), FLT3 D835(−)
2 FLT3-ITD(+), FLT3 D835(−), CEBPA(+), IDH1(−),IDH2(−), KIT(−), RAS(−) NPM1(−)
FLT3 ITD(+), FLT3 D835(−), ABL1(−)
3 NA FLT3 ITD(+), NRAS(+)a, RUNX1(+)a,WT1(+)a, ABL1(−)
4 NPM1(+), IDH1(+), JAK2(−), KIT(−), FLT3(−), IDH2(−), KRAS(−), NRAS(−)
NPM1(+), IDH1(−), IDH2(−), FLT3(−),KIT(−), CEBPA(−)
5 NRAS(+) NA
6 NRAS(+)a GATA2(+)a NRAS(+)
7 NA ABL1(+), NRAS(−), KIT(−), NPM1(−),CEBPA(−)
8 FLT3-ITD(−), FLT3 D835(−), KRAS(−), NRAS (−) NA
9 NRAS(−), KRAS(−) NA
10 FLT3-ITD (+) FLT3 D835(−), NPM1 (+) FLT3-ITD(+), FLT3 D835(−)
11 Negativea FLT3-ITD(−), FLT3 D835(−)
12 FLT3-ITD(−), FLT3 D835(−), KIT(−), NPM1(−), RAS(−), CEBPA(−), IDH1(−), IDH2(−)
NA
13 FLT3-ITD(−), FLT3 D835(−), KIT(−), NPM1(−), RAS(−)
NA
14 NA JAK2(+)b, EZH2(+)b, CEBPA(+)b
15 FLT3-ITD(−), FLT3 D835(−), RAS(−) NA
16 FLT3-ITD(−), FLT3 D835(−), RAS(−) ABL1(−)
17 NA Negativea, ABL1(−)
18 NA NA
19 NA TP53(+)a
Ph Philadelphia chromosome, NA not available. Common mutations before and at/after emergence of Ph are underlinedaTested with next-generation sequencing-based analysis with 28 gene panelbTested with next generation sequencing-based analysis with 53 gene panel
Secondary Philadelphia chromosome acquired during therapy
Discussion
We reported 19 patients with Philadelphia chromosome-negative de novo acute myeloid leukemia, myelodysplasticsyndrome, B lymphoblastic leukemia, and T lymphoblasticleukemia who secondarily acquired the Philadelphia chro-mosome during therapy. The emergence of secondary Phi-ladelphia chromosome-positive clones by karyotypingoccurred concomitantly with relapsed or refractory diseasein de novo acute leukemia or secondary acute myeloidleukemia arising from myelodysplastic syndrome. In mostpatients, the BCR-ABL1 transcript subtype was of the e1a2(encoding P190 BCR-ABLl protein), and the Philadelphiachromosome-positive disease and the original leukemiawere clonally related. The Philadelphia chromosome-positive clones were the dominant clones in more thanhalf of the patients when secondary Philadelphia chromo-some emerged. Despite the absence of the Philadelphiachromosome-positive clones by karyotyping in 6 patients,13 of 15 patients with follow-up information died withrefractory disease after a median follow-up of 3 months,including one patient with therapy-related acute myeloidleukemia.
Secondary Philadelphia chromosome acquired duringtherapy of myeloid or lymphoid neoplasms is rare; 36 suchcases have been reported in the form of single-case reportsin the English literature (Table 4 and Supplemental Table 2)[20–53]. We reviewed these published cases and reclassi-fied them, if necessary or possible, according to the 2016update of World Health Organization classification [63].The 36 cases included the following: acute myeloid leuke-mia (n= 14), myelodysplastic syndrome (n= 10), B lym-phoblastic leukemia (n= 6), T lymphoblastic leukemia (n= 5), and chronic myelomonocytic leukemia (n= 1). Therewere 20 men and 16 women with a median age of 43 years(range, 3–71 years), approximately 10 years younger thanthat in our study. Similar to our cases, secondary Phila-delphia chromosome was detected at relapse or at a terminalstage of refractory disease in patients with acute leukemia.In patients with myelodysplastic syndrome, the Philadelphiachromosome emerged at time of or after acute transforma-tion in 8 of 10 patients. The median interval from initialdiagnosis to secondary acquisition of the Philadelphiachromosome was 15 months (range, 1–120 months).Twenty-one patients had an abnormal karyotype at initialdiagnosis or anytime during therapy before secondary Phi-ladelphia chromosome emerged; the abnormalities presentbefore the emergence of secondary Philadelphia chromo-some were also observed in the Philadelphia chromosome-positive clones in 19 patients, including one patient withNRAS mutation observed before and at emergence of thePhiladelphia chromosome. Additionally, one patient with anormal karyotype before secondary acquisition of the
Philadelphia chromosome had NPM1 mutations before andat emergence of the Philadelphia chromosome. The BCR-ABL1 fusion transcript encoded P190 in 16/24, P210 in 5/24, and both P210 and P190 both in three patients. Of note,in the latter three patients, the Philadelphia chromosomewas not detected by karyotyping but P210-encoding tran-scripts were detected by reverse transcription-quantitativePCR, and P190/e1a2 transcripts emerged later 3, 4, and14 months before the detection of the Philadelphia chro-mosome by karyotyping, suggesting that the secondaryPhiladelphia chromosome encoded P190. BCR-ABL1 at theonset of the disease was detected in only 2 of 17 patientstested with reverse transcription-quantitative PCR, FISH, orboth. Twenty-three patients had treatment information
Table 4 Summary of clinicopathologic characteristics of patients withsecondary Philadelphia chromosome
Currentstudy
Previous studies[20–53]
Overall
Case number 19 36 55
Age: median; range(yrs)
53 (18–78) 43 (3–71) 48 (3–78)
Interval: median;range (mo)
18 (6–72) 15 (1–120) 16 (1–120)
Disease distribution (n)
AML 11 14 25 (45.5%)
MDS 5 10 15 (27.3%)
B-ALL 2 6 8 (14.5%)
T-ALL 1 5 6 (10.9%)
CMML 0 1 1 (1.8%)
BCR-ABL1 subtype
P190 12/14 16/24 28/38(73.7%)
P210 2/14 5/24 7/38(18.4%)
P190, P210 0 3/24 3/38 (7.9%)
Clonal relatednessa
By karyotype 7/9 19/21 26/30(86.7%)
By molecularmutation
4/5 2/2b 5/6 (83.3%)b
Total 11/14 20/22b 31/36(86.1%)
Median OS after Ph(mo)
3.1 4.5 4
Ph Philadelphia chromosome, Age age at initial diagnosis, yrs years,Interval interval time from initial; diagnosis to the emergence of Ph,mo months, n numberaComparison between diseases at any time before the emergence of Phand at the emergence of PhbIncluding 1 patient with clonally related diseases before and at theemergence of Ph by karyotyping
H. Kurt et al.
available, 21 patients received chemotherapy, 8 receivedtyrosine kinase inhibitors, and 6 received allogeneichematopoietic stem cell transplantation. Of 33 patients withfollow-up information available regarding the disease sta-tus, 30 had relapsed or refractory disease and 26 were deadat last follow-up, with a median follow-up of 5 months(range, 1–22 months). For the 16 patients with follow-upinformation available regarding the evolution of the Phila-delphia chromosome-positive clones, the Philadelphiachromosome-positive clones were persistent and/or becamethe major clone in most patients despite intensive che-motherapy, and only 3 patients achieved cytogeneticremission [32, 52, 53].
The emergence of secondary Philadelphia chromosomecan be explained by multiple mechanisms. It may indicateclonal evolution and disease progression. This hypothesis issupported by the findings that the diseases before and afterthe emergence of secondary Philadelphia chromosome wereclonally related by karyotyping or molecular analyses in thevast majority of patients (86%) in our series and in patientsreported previously (Table 4 and Supplemental Table 2).This apparently underestimates the clonal relatedness giventhe limited panel used to detect molecular mutations.Alternatively, in a subset of patients the emergence ofsecondary Philadelphia chromosome could be due to theexpansion of a minute Philadelphia chromosome-positivesubclone not detectable initially by cytogenetic methods.The detection of the same transcript subtype of e1a2 beforeand at time of emergence of the Philadelphia chromosome-positive subclones in three patients (#1, 11, and 18) in thisstudy would substantiate this theory. In all three patients,interestingly, the Philadelphia chromosome-positive sub-clones clonally related to the previous disease before theemergence of secondary Philadelphia chromosome.
The persistence or refractoriness of disease despite thedisappearance of secondary Philadelphia chromosome-positive clones in some patients suggests that BCR-ABL1is not essential for the maintenance of the leukemic process.However, the persistence of Philadelphia chromosome-positive clones despite chemotherapy and/or tyrosine kinaseinhibitors in some patients and predilection of the e1a2(P190) subtype rather than the typical b2a2/b3a2 (P210) inmost patients support a role of BCR-ABL1 in disease pro-gression. Both P210 and P190 BCR-ABL1 fusion transcriptsresult in new chimeric proteins with increased tyrosinekinase activity. However, P190 was shown to have at leastfivefold higher tyrosine kinase activity than P210 in amurine model [64]. Transgenic mice bearing the e1a2(P190) fusion transcript develop acute leukemia [65],whereas transgenic mice bearing P210 develop chronicmyeloid leukemia [66]. Patients with myelodysplastic syn-drome with P190 at initial presentation show rapid pro-gression to acute myeloid leukemia [67]. P190 is also
associated with transformation of chronic myeloid leukemiato a more aggressive terminal phase disease [68]. In addi-tion, patients with de novo acute myeloid leukemia withP190 have a higher rate of relapse than patients with P210[19]. Overall, these findings correlate with our finding thatP190 is highly associated with disease progression inmyeloid and lymphoid neoplasms.
Adding tyrosine kinase inhibitors to the therapeuticregimens has significantly altered the outcome of patientswith chronic myeloid leukemia [69, 70] and Philadelphiachromosome-positive acute lymphoblastic leukemia [71,72], and the efficacy has also been shown in Philadelphiachromosome-positive de novo acute myeloid leukemia [19].It is worth mentioning that tyrosine kinase inhibitors areeffective in rare cases of myelodysplastic syndrome with thePhiladelphia chromosome [73] and rare cases with con-current BCR-ABL1 and CBFB rearrangements [31, 74, 75].However, the effect of tyrosine kinase inhibitors along withor in place of chemotherapy in patients with late-acquiredPhiladelphia chromosome in relapsed or refractory diseaseis not well understood. We reported seven such patientstreated with tyrosine kinase inhibitors. In this study, eradi-cation of the Philadelphia chromosome-positive clonesdetected by FISH analysis was observed in five of sixpatients with follow-up information although four of themhad refractory Philadelphia chromosome-negative disease.Eight such patients reported in the literature received tyr-osine kinase inhibitors; seven showed partial or completeresponse to tyrosine kinase inhibitors although four patientshad relapsed or refractory disease at last follow-up. Thesefindings show that incorporating tyrosine kinase inhibitorsin the treatment is an effective approach to treat the Phila-delphia chromosome-positive clones in most patients.Overall however, prognosis of these patients is still poordue to other factors.
In conclusion, the Philadelphia chromosome, usuallyseen as a primary change in chronic myeloid leukemia, canalso occur secondarily as a late-developing chromosomalabnormality during therapy of myeloid and lymphoid neo-plasms. The transcript subtype associated with the late-occurring Philadelphia chromosome is overwhelmingly ofthe e1a2 (P190), and the disease before and after theemergence of the Philadelphia chromosome are clonallyrelated. Incorporating tyrosine kinase inhibitors into treat-ment may eradicate the Philadelphia chromosome-positiveclones and could potentially change the disease prognosis ina small subset of patients, but most patients do not respondto the treatment and the overall survival is poor.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict ofinterest.
Secondary Philadelphia chromosome acquired during therapy
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Supplemental Table 1. Complete blood count and differential count at time of Philadelphia chromosome emergence
No. Initial Dx
Hgb (g/dl)
PLT (K/μl)
WBC (K/ μl)
Neutrophil (%)
Immature Granulocyte (%)
Lymphocyte (%)
Monocyte (%)
Eosinophil (%)
Basophil (%)
Blast (%)
1 AML 14.6 210 8.2 39 3 18 23 1 0 16
2 AML 10.1 19 2.5 11 0 76 1 11 1 0
3 AML 8.8 43 53.4 10 2 2 14 0 1 71
4 AML 11.5 226 9 66.3 1.6 15.5 14.9 1.1 0.6 0
5 AML 8.4 62 2.7 22 0 52 13 2 3 8
6 AML 9.7 20 25.7 44 3 9 2 0 0 42
7 AML 9.8 55 37.7 1 0 1 1 0 1 96
8 AML 8.8 19 8 2 2 24 6 0 0 66
9 AML 10.6 16 31.7 9 23 4 0 0 0 64
10 AML 8.9 15 2.1 68.9 3.4 13.6 12.6 1.5 0 0
11 AML 9.6 104 13.9 3 0 24 7 1 0 65
12 MDS 9.7 23 3.8 28 0 58 1 1 0 12
13 MDS 8.9 202 89.2 29 8 13 18 7 2 23
14 MDS 9.9 57 2.4 79 2 10 9 0 0 0
15 MDS 9.0 12 1.0 6 3 78 9 0 2 2
16 MDS 11.4 27 28.1 2 0 3 8 0 0 87
17 B-ALL 9.5 36 1.2 29 0 66 0 0 0 5
18 B-ALL 9.1 8 3.6 4 0 66 2 4 0 24
19 T-ALL 10.3 29 27.9 55 3 2 2 1 1 36
Abbreviations: Ph, Philadelphia chromosome; Dx, diagnosis; Hgb, hemoglobin; PLT, platelet; WBC, white blood cell; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; B-ALL, B -lymphoblastic leukemia; T-ALL, T -lymphoblastic leukemia.
Supplemental Table 2. Clinical, cytogenetic/FISH and molecular features of published cases with secondary Philadelphia chromosome
Ref Age/ sex
Initial dx
Cytogenetic/FISH and molecular data before emergence of Ph
Interval (months) Dx at Ph detection Cytogenetic/FISH and molecular data
at and after emergence of Ph BCR-ABL1 transcript Tx Disease status, outcome,
survival after Ph
Kohn19 38/F AML 1) Onset: NA 2) stable (4 mo): 45,XX,-6 [30] 7 Refractory AML 1) Initial: 45,XX,-6[20]/45,XX,-6,-22,+Ph1[2]
2) 2 wk after Ph: 45,XX,-6,-22,+Ph1[22] NA Chemo Refractory, AML, died, 2 mo
Abe20 33/F AML 1) Onset: 46,XX[18] 2) 1st relapse (11 mo): 46,XX[4] 12 Relapsed / persistent
AML Initial: t(9;22)(q34;q11)[7] NA Chemo Relapsed/ persistent AML, died, 14 mo
Abe20 40/M AML Onset: 46,XY[44] 1 Persistent AML
1) Initial (8% blasts): t(9;22)(q34;q11)[37] 2) 1 wk after Ph (52% blasts): t(9;22)(q34;q11)[14] 3) 4 wk after Ph (11% blasts): No Ph 4) 7 wk after Ph (52% blasts): No Ph 4) 13 wk after Ph (96% blasts): No Ph
NA NA Refractory AML, died, 5 mo
Smadja21 62/M AML 1) Onset: NA 2) stable disease (6 mo): 46, XY[19] 17 Progression of AML
1) Initial: 46.XY,Ph' (100%)[33/33] 2) PR (22 mo): 46,XY,Ph' (60%)4 6.XY (30%)/4 7,XY,+11 (10%) 3) PR (32 mo): 46,XY,Ph' (26%)/ 46,XY (38%)/ 47,XY,+ 11 (36%) 4) Refractory (35 mo): 46,XY,Ph' (100%)
NA Chemo Persistent/refractory AML, died, 21 mo
Jacobsen22 62/F AML 1) Onset: 46,XX[49] 2) CR (2 mo): 46,XX 3) 1st relapse (32 mo): NA
40 2nd relapse 1) Initial: 46, XX[17]/46, XX,t(9;22)(q34;q11)[12 ] 2) persistent AML (1 mo after chemo):46,XX[20] NA Chemo Refractory; died; shortly
after
Vandenberghe23 28/F AML
1) Onset: 45,XX-7,ins(12;3)(q14;q22q27); Q-PCR (-), NRAS (+) 2) post-alloSCT (3 mo): 46, XY[10] 3) 1st relapse (8 mo): NA; NRAS (+) 4)PR (10 mo): NA; NRAS (+)
13 Refractory Initial: 45,XX-7,ins(12;3)(q14;q22q27)[3]/45,XX-7,t(9;22)(q34;q11),ins(12;3)(q14;q22q27)[7]; NRAS (+) p190 NA Persistent AML, died, NA
(shortly after)
Shimamoto 24 Fujimura25 58/F AML
1) Onset: 46, XX,t(7;11)(p15;p15)[10]; Q-PCR (-) 2) PR (5 mo): 46,XX[17]46, XX,t(7;11)(p15;p15)[3] 3) Refractory (8 mo): 46, XX,t(7;11)(p15;p15)[19]/46,idem,t(2;10)(q22;q26)[1]; Q-PCR (-) 4)PR (15 mo): 46, XX[9]/46, XX,t(7;11)(p15;p15)[5]
16 Refractory Initial: 46, XX[3]/46, XX,t(7;11)(p15;p15)[4]/46,idem,t(9;22)(q34;q11)[4]/46,idem, add(12)(p12)[1]
p190 Chemo Persistent/refractory AML, died, 3 mo
Matsue26 63/F AML 1) Onset: 46,XX; Q-PCR (-) 2) 1st relapse (10 mo): 46,XX; Q-PCR (-) 17 Relapsed/ refractory
AML Initial: 45,XX,-7,t(9;22)(q34;q11)[20] p190 Chemo Refractory AML, NA, NA
Chen27 16/M AML Onset: 45,XY,-7,t(10;14)(q11.2;q11.2) [8]/44,XY,add(1)(p36),t(6;6)(p11.2;q13),-7,del(13)(q13),add(14)(p11),-16 [7]/42,XY,add(1)(q44),-4,-5,-7,-8,-9,add(9)(p22),-11,add(14)(q32),-15,-19,-22,+5mar [5]
1 Post-alloSCT
1)initial: 45,XY,-7,t(9;22)(q34;q11.2),t(10;14) [8]/40~45,XY,-7,inc [12]; FISH (+), 83.7% 2)Refractory (3 mo): 45,XY,t(3;17)(q26;q23),-7,t(9;22),t(10;14)[18]/44,XY,-7,inc [2] 3)refractory (7 mo): 45,XY,t(3;17),-7,t(9;22),t(10;14) [20]
p190 NA Refractory, alive, lost in F/U (6 mo)
Najfeld28 62/F AML 1) Onset: 46, XX[8]/45,X,-X,t(8;21)(q22;q22)[20] 2)1st relapse (14mo): 46, XX[33]/46,XX,t(8;21)[2] 18 Relapsed/ persistent
AML
1) Initial: 46,XX[4]/46,XX,del(5)t(8;21)[8]/46,XX,del(5)t(8;21),t(9;22)(q34;q11)[1 ] 2)CR (20 mo): 46,XX 3) 2nd relapse (21 mo): 46,XX[8]/ 46,XX,del(5)t(8;21),t(9;22)[40]/46,X,del(X)(p11p21),del(5),t(8;21),t(9;22)[3]/46,XX,der(1)t(1;7)(p34.2;q22),del(5),del(7)(q22),t(8;21)t(9;22)[4]
p190 chemo Relapsed/ refractory, died, 8 mo
Shah29 3/F AML
1) Onset: 47,XX, +8[16]; FISH (-) 2) 2nd induction (3 mo): 46,XX,t(11;15)(p13;q26),del(20)(q11.2) [9] 3) refractory (12 mo): 46,XX,t(11;15)(p13;q26),del(20)(q11.2)[20]; FISH (+) , 1 metaphase 4) refractory (13 mo): 46,XX,t(11;15)(p13;q26),del(20)(q11.2)[1]; FISH (+) , 4/176
14 Refractory AML
1) Initial: 46,XX,t(9;22)(q34;q11.2)[7]46,XX,t(11;15)(p13;q26),del(20)(q11.2)[5]; FISH (+), 34/200 2) Persistent, 3 wk after Ph: 46,XX,t(9;22)(q34;q11.2)[23]; FISH (+), 125/200
p190 Imatinib Refractory AML, died, 4 mo
Bacher30 71/M AML Onset: 46, XY; NPM1 (+) 22 Relapsed/ refractory AML
1) Initial: 45,XY,der(7;21)dic(7;21)(q21;q22)ins(7;21)(q11;q?q?) [10]/46,XY,t(9;22)(q34;q11)[3]/46,XY[8]; NPM1 (+) 2) refractory: Ph[17/20]; Q-PCR (+), 45%; NPM1 (+)
p190 NA Relapsed/refractory, died, 4 mo
Aoki31 48/F AML 1) Onset: 46, XX, del(7)(q11.2) (18/20) 2) 1st relapse (11 mo): 46,XX 3) 2nd relapse (19 mo), post-AlloSCT: NA
23 Relapsed/ progressive
1) Initial: 46, XX, del (7)(q?),t(9; 22), del(11)(q?) (2/20 cells) 2) CR (chemo + alloSCT): NA 3) 3rd relapse (33 mo): 46, XX, del (7)(q?),t(9; 22), del(11)(q?) (1/20 cells); FISH (+), 5/100
NA
Chemo, alloSCT; chemo, imatinib, dasatinib, nilotinib
CR, died, 22 mo
Neuendorff32 65/M AML 1) Onset: t(6; 11)(q27;q23) (20/20) 2)1st relapse (11 mo): NA, MLL-AF6 Q-PCR (+); BCR-ABL1 Q-PCR (-)
NA 2nd relapse (15 mo after alloSCT)
1) Initial: 46,XY, t(6; 11)(q27;q23), t(9; 22)(q34;q11) [24] /46,XY, t(6; 11)(q27;q23) [1] ; FISH (+), 74%; Q-PCR (+) 2) chemo with no response: NA 3) 1 mo nilotinib, persistent disease: 46,XY, t(6; 11)(q27;q23)(dominant clone)/46,XY, t(6; 11)(q27;q23), del(20q)[1]; FISH (+), 3%
p190 Chemo, nilotinib (1mo)
Relapsed/ refractory; alive, NA
Verhoef33 63/M MDS Onset: 46, XY 18 MDS-EB-2 (18% blasts) Initial: 46,XY,t(9;22)(q34;q11)(100%) NA NA Refractory, alive, 3 mo
Kohno34 54/M MDS 1) Onset: 46,XY[20] 2) MDS EB-1 (24 mo): 46,XY,20q-[20] 30 B-ALL transformation Initial: 46, XY,t(9;22)(q34;q11),20q-[18]/46,XY,20q-[2] p190 Chemo Persistent, NA, NA
Roumier35 53/F MDS 1) Onset: del5q 2) 16 mo before Ph: del5q; FISH (-) 60
CMML-2 (11% blasts) (WBC:22, mono37, eos 4, immature 2, no splenomegaly)
Initial: 44, XX, del(5) (q13q33), add(13)(p11), -17, -18,add(20) (q12), -21, +mar1(4)/ 44-45, idem, (0-1)inv(1) (p11q25), t(9;22)(q34;q11), +(0-1)der(22) t(9;22) (q34;q11)
p190 NA Persistent CMML-1, died, 2 mo
Bacher30 64/F MDS Onset: del5q 120 sAML Initial: 46,XX,del(5)(q14q34),t(9;22)(q34;q11)[11]/45,XX,del(5)(q14q34),t(9;22)(q34;q11),dic(16;17)(q11;p11)[4]/46,XX[5]
p210 Imatinib, dasatinib, alloSCT
Relapsed AML; alive, 15 mo
Kelemen36 66/M MDS 1) Onset: del20q 2) sAML (8 mo): 46,XY,del(7)(q22q34),del(20)(q11.2;q13.1)[16]/46,XY[4]
NA 1st relapse (3 mo after alloSCT)
Initial: 46,XY,del(7)(q22q34),t(9;22)(q34;q11.2),del(20)(q11.2q13.1)[18]/46,idem, t(X;10)(q24;q11.2)[2]--FISH 91%
NA Chemo Relapsed/persistent AML, died, 8 mo after AML transformation
Yamashita37 39/M MDS-EB-1
1) Onset: 46,XY,t(3;3)(q21;q26)[19]/46,XY[1];Q-PCR (-) 2) sAML (3 mo): 46,XY,t(3;3)(q21;q26)[20]; Q-PCR p210 (+) 16 Refractory AML 46,XY,t(3;3)(q21;q26)[50]/46,XY,del(1)(q22),r(3;3)(q21;q26),-
16[6]/46,XY,t(3;3)(q21;q26),t(9;22)(q34;q11)[3] p190 (p210) Chemo Refractory, died, 2 mo
Nakamura38 3/M MDS-EB-2
1) Onset: 46,XY[30]; Q-PCR (-) 2) sAML (23 mo): 46,XY[30] 32 Refractory AML Initial: 46.XY,t(9:22)(q34:q11) p210 NA NA
Katsuno39 39/M MDS-EB-2
1) Onset: 46,XY,t(3;3) (q21;q26)[19]; Q-PCR (-) 2) sAML (3 mo): 46,XY,t(3:3)( q21;q26) [20]; Q-PCR p210 (+) 17 Refractory AML Initial: 46,XY,t(3;3) (q21:q26) (50)/46,XY,del(1)( p22),t(3;3)( q21;q26),-
16[6]/46,XY,t(3;3)( q21:q26),t(9;22(q34:q11)[3] p190, p210 Chemo Persistent AML, died, 14 mo
Keung40 71/M MDS-EB-2 Onset: 46,XY 5 sAML Initial: 46,XY,t(9;22)(q34;q11)[20] NA Chemo Persistent AML, died, 4 mo
Prebet41 48/F MDS-EB-2
1) Onset: +8 (12/20); FISH (-); Q-PCR (-) 2) relapsed s AML (8 mo): +8 12 2nd AML relapse Initial: 46,XX,del(5)(q21q32),t(9;22)(q34;q11),
del(12)(q21q24),del(13)(q13q32),add(15)(q23),add(16)(q13) p190 Chemo, imatinib PR, died, 3 mo
Hamaguchi42 45/F CMML-2
1) Onset: 46,XX,t(3;3)(q21;q26)[20] 2) Persistent sAML (10 mo): NA; Q-PCR p210 (+) 14 Refractory sAML Initial: 46,XX,t(3;3)(q21;q26),t(9;22)(q34;q11)[19] p190, p210 NA Progressive AML, died, 4
mo
Miller43 5/M T-ALL Onset: 46,XY,9p-[19] 4 1st relapse 1) Initial: 46 XY,9p-, 6q-,t(9q+;22q-)[20] 2) PR (8 mo): 46,XY[7]/46 XY,9p, 6q-,t(9q+;22q-)[1] 3) refractory (9 mo): 46 XY,9p, 6q-,t(9q+;22q-)[12]
NA Chemo Progressive ALL, died, 7 mo
Coad44 7/M T-ALL Onset: 46,XY,der7t(7;9)(q3?4;q22),-9,+add(12)(p11q2?2)[21]/46,XY[1] 13 1st relapse Initial: 47,XY,der7t(7;9)(9;22)(q3?4;q22q34;q11),-
9,+der(22)t(9;22)(q34;q11),+mar[13] p210 Chemo, alloSCT
Relapsed ALL, died, 2 wk after 2nd relapse
Tsuchiya45 12/M T-ALL Onset: 46, XY,del(9)(p?22)[3]/46,XY[1]; Q-PCR (-); SB clonal TCR-B (+) 6 1st relapse
Initial: 46, XY,del(9)(p?22),t(9;22)(q34;q11)[1]/46,XY,del(10)(q34),add(13)(p13)[1]/46,XY[18]--same TCRB clone by Southern Blot
p210 Chemo, alloSCT
Persistent ALL, died, shortly after
Tchirkov46 5.5/M T-ALL Onset: 46,XY[26]; Q-PCR (-) 7 1st relapse
1) Initial: NA; FISH (+), 29%; Q-PCR (+), 4% 2) clinical remission: 46, XY[16]; FISH(+), 4.5%; Q-PCR (+) 3)2nd relapse (10 mo): 46, XY[16]; FISHinterphase(+), 25%; FISHmetaphase (+),
4/12; Q-PCR (+), 52% p210 NA Progressive ALL, died,
7 mo
Campbell47 26/M T-ALL Onset: 45,XY,del(6)(q 15q241,der(9)t(9:14)(p 13;q11),-14[14]/46.XY[15]; Q-PCR (+); FISH (+), 25/427(6%) NA 1st relapse
Initial: 45,XY,add(5)(q31),del(6)(q15q25),t(8;14)(q24; q11),der(9)t(9;14)(p13;q11),-14[3]/45, idem,add( 16)(p1 3)[3]/46,XY,del(1 ) (q42),+der(9)t(9;14)(p13;q11)t(9;22)(q34;q11),-14,der( 22)t(9;22)(q34;q 1 1 )[ 1 1]/46, XY [4]
p210 NA NA, NA, 13 mo after diagnosis
Sessarego48 45/F B-ALL 1) Onset: 46, XX[21] 2) 1st relapse (8 mo): 46, XX 13 2nd relapse Initial: 46, XX,t(9;22)(q34;q11)[15]/46,XX[9] NA NA Relapsed/persistent
disease, died, 1 mo
Tsuchiya45 10/M B-ALL 1) Onset: NA, Q-PCR (-); SB clonal IgH (+) 2) 1st relapse (9 mo): 46, XY [20] 16 Relapsed/ persistent
Initial: 44,t(X;11)(p11;p15),-Y, add(3)(q29),der(8)t(1;8)(q21;q24),del(9)(p13), t(9;22)(q34;q11), -12,der(?)t(12;?)(q13;?),-16[6]#SB clonal IgH (+)
p190 NA Persistent disease, died, 2 wk
Inokuchi49 52/F B-ALL Onset: 46,XX[20] 2 Refractory
1) Initial: 46,XX,t(9;22)(q34;q11)[6]/other nonspecific aberration with 46,XX,t(9;22)(q34;q11)[14] 2) 1st relapse (6 mo): 46,XX,t(9;22)(q34;q11),-20,add(21)(q22)[18]# 3) 2nd relapse: 46,XX,der(5)(5pter ok 5q11.2::22q11ok22qter), der(9)(9pterok9q34::5q11.2ok5qter),del(10(q11.2),inv(12)(p13q13), der(22)(22pterok22q11::9q34ok9qter),del(22)(q11)[11]#
p190 NA Relapsed/refractory, died, 8 mo
Chen50 23/F B-ALL 1) Onset: 48,XX,+X, +14[7]/46,XX[10]; Q-PCR (+); SB clonal IgH (+) 2) CR (2 mo): 46,XX[20]; Q-PCR (-)
15 1st relapse
1) Initial: 47,XX,add(9)(p22),+mar[5]/47,XX,add(9)(p22),t(9;22)(q34;q11),+mar[13]; IgH clone (-); Kappa clone (+) 2) CR (chemo,1 mo after Ph): 46,XX[20]; Q-PCR (-) 3) 2nd relapse, after 1 mo imatinib, 2 mo after Ph: 47,XX,add(9)(p22), mar[13]/46,XX[6]; Q-PCR (+) 4) post-alloBMT day 30, 3 mo after Ph: 46,XX[20]; Q-PCR (-) 5) 3rd relapse: 47,XX,add(3)(q21),inv(3)(q21q26),add(4)(q28), add(9)(p22),(9;22)(q34;q11),add(12)(p13),+mar[13]/46,XX[1]; Q-PCR (+); Kappa clone(+)
p190 Chemo, imatinib, alloSCT
Relapsed leukemia, died, 5 mo
Hato51 29/M B-ALL Onset: 46,XY[20]; Q-PCR (+); FISH (+), 12.5% NA CR
1) Initial: t(9;22)(q34;q11)[2/20]; FISH (+), 0.9% 2) after alloSCT: 46,XY; FISH (-); Q-PCR (-) 3) 7 mo after alloSCT: Q-PCR (+) 4) 1st relapse (11 mo after alloSCT): t(9;22)(q34;q11)[10/20]; FISH (+), 39%; Q-PCR (+) 5) CR (chemo + imatinib): NA 5) 2nd alloSCT: Q-PCR (+); FISH (-)
p190 Chemo, imatinib, alloSCT
CR, alive, NA
Adriana52 19/M B-ALL 1) Onset: 46,XY[20]; FISH (-) 2) clinical remission (4 mo): NA; Q-PCR (+), 0.08%; FISH (-) 7 1st relapse
1) Initial: 46,XY[4]/46,XY,+6+4-9-12,19,+21,der(22)t(9;22)(q34;q11)[4]/73,XXYY,t(9;22)(q34;q11,der(22)t(9;22)(q34;q11)[17]; FISH (+), 90% 2) morphologic remission: 46,XY[20]; FISH 10%
p190 Chemo, dasatinib
Morphologic remission, lost in F/U, 1 mo
Abbreviations: AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; EB, excess blast; CMML, chronic myelomonocytic leukemia; ALL, acute lymphoblastic leukemia; CR, complete remission; PR, partial remission; alloSCT, allogeneic stem cell transplant; SB, Southern blot; Q-PCR, reverse transcription quantitative polymerase chain reaction; IgH, immunoglobulin heavy chain; TCR-B, t-cell receptor beta; Ph, Philadelphia chromosome; chemo, conventional chemotherapy; NA, not available; M, male; F, female; FISH, fluorescence in situ hybridization studies; F/U, follow-up; mo, months; wk, weeks. #Dominant clone, please refer to original article for complete karyotype.