Abstract

The most common BCR-ABL transcripts in chronic myeloid leukemia (CML) are e13a2(b2a2) and e14a2(b3a2). Other transcripts such as e1a2 are rare and their outcome with tyrosine kinase inhibitors (TKI) therapy is undefined. We analyzed 1292 CML patients and identified 14 with only e1a2 transcripts, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP). Of the CP, 4 achieved complete hematologic response (CHR); 2, complete cytogenetic response (CCyR); 2, partial cytogenetic response (PCyR), and 1 did not respond to imatinib. Five patients progressed to myeloid BP (3), lymphoid BP (1), or AP (1). The AP patient received various TKIs sequentially and achieved only CHR. BP patients received hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone) plus imatinib/dasatinib or idarubicin plus cytarabine (Ara-C); 2 did not respond, 1 had CCyR, and 1 short-lasting complete molecular response (CMR). Overall, cytogenetic responses lasted 3 to 18 months; only 2 achieved major molecular response (MMR) on TKI. P190BCR-ABL CML is rare and is associated with an inferior outcome to therapy with TKI. These patients need to be identified as high-risk patients.

Introduction

The Philadelphia chromosome (Ph), t(9;22)(q34;q11.2), in chronic myeloid leukemia (CML) is transcribed into a fusion gene, BCR-ABL. The breakpoint in BCR gene on chromosome 22 usually occurs in the major breakpoint cluster region (M-bcr) between exons e12-e16 (formerly named b1-b5), whereas breakpoints in ABL gene on chromosome 9 happen in exon a2, resulting in fusion transcripts e13a2(b2a2) and e14a2(b3a2).1  Rarely, the minor breakpoint cluster region (m-bcr) may be involved with a resultant fusion transcript e1a2.2-5  Other transcripts such as e19a2,2,6,7  e2a2,8  e1a3, e6a2, e13a3(b2a3), and e14a3(b3a3)9,10  occur less frequently. The e13a2(b2a2)/e14a2(b3a2) fusion transcripts encode for a 210-kDa protein (P210BCR-ABL), whereas the e1a2 encodes for a 190-kDa protein (P190BCR-ABL), and the e19a2 encodes for a 230-kDa protein (P230BCR-ABL).

In CML, the e1a2 transcripts may coexist with e13a2(b2a2)/e14a2(b3a2),11  but CML expressing only e1a2 transcripts (from here on referred to as P190BCR-ABL CML) is uncommon, and outcome of patients with this transcript alone in the era of tyrosine kinase inhibitors (TKIs) is not well known. Although there are anecdotal reports of patients with P190BCR-ABL CML treated with imatinib2  or other therapies,3-5,11-14  to our knowledge, there are no published series of data on efficacy of imatinib or other TKIs in CML with this transcript. We performed this study to investigate the frequency of P190BCR-ABL CML, the clinical characteristics of patients with this entity, and their outcome after treatment with TKI.

Methods

The records of all patients with CML treated with TKI at M. D. Anderson Cancer Center from January 2000 to November 2008 were reviewed to identify patients with only e1a2 BCR-ABL fusion transcripts consequent to breakpoints in minor bcr. Patients with e1a2 coexisting with e13a2(b2a2) and/or e14a2(b3a2) were excluded from this analysis. The criteria for chronic phase (CP), accelerated phase (AP), and blast phase (BP) were as previously described.15  All patients were enrolled in various studies approved by the institutional review board of M. D. Anderson Cancer Center and signed informed consents were in accordance with the Declaration of Helsinki.

Patients had complete blood counts and blood chemistry before the start of therapy and every month for the first 3 months, then every 3 months for 9 months, and then every 6 months. Cytogenetic response was assessed by G-banding assessed in the bone marrow with at least 20 metaphases counted. The BCR-ABL fusion transcripts were analyzed using reverse transcription quantitative polymerase chain reaction assay that detects e1a2, e13a2(b2a2), and e14a2(b3a2) transcripts in a single tube and is normalized to ABL1, with BCR-ABL transcript type determined by subsequent capillary electrophoretic separation of the fluorochrome-labeled products.16  Both cytogenetic and molecular response assessments were performed at baseline, every 3 months for the first 12 months, and then every 6 months. Response and relapse criteria were as previously reported.17,18 

Event-free survival (EFS) was measured from the start of each therapy until loss of complete hematologic response (CHR) or major cytogenetic response, progression to the AP or BP, or death from any cause during treatment. Overall survival was defined from date of CML diagnosis to date of death or last follow-up.

Results and discussion

Fourteen (1%) of the 1292 CML patients treated with TKI, during the study period had P190BCR-ABL CML. At the time of diagnosis, 9 patients were in CP, 4 in BP (1 myeloid [MyBP], 3 lymphoid [LyBP]), and 1 in AP (based on clonal evolution–double Philadelphia and t(9;17)(q32;q12), +8, +10, +19, +21). Patient characteristics are shown in Table 1. The median age at the time of diagnosis was 60 years (range, 28-86 years). The median follow-up since the diagnosis of CML is 40 months (range, 3-109 months).

Table 1

Patient characteristics and overall responses to treatment at CML diagnosis with e1a2 BCR-ABL fusion transcripts

Characteristic CP, n = 9 AP (CP + CE), n = 1 BP, n = 4 
No. of patients 1:MyBP, 3:LyBP 
Median age at CML diagnosis, y (range) 60 (28-86) 46 60.5 (47-66) 
Median follow-up after CML diagnosis, mo (range) 57 (3-109) 55 12.5 (8-40) 
Median time from CML dx to treatment, mo (range) 0.5 (0-2) 0.25 (0-0.5) 
IFN therapy before TKI, no. (%) 3 (33) — — 
TKI as first line (alone or in combination), no. (%) 6 (67) 1 (100) 3 (75), all LBP 
Evolution into AP 1 (11) — — 
Evolution into BP 4 (44) n/a 
Median overall survival, mo (range) 56 (3+ to 109) 55+ 13 (8-40) 
Number surviving 5 (56) 1 (100) 
BCR-ABL/KD mutations at relapse 2* of 7 (29) NA 2 of 2* (100) 
Characteristic CP, n = 9 AP (CP + CE), n = 1 BP, n = 4 
No. of patients 1:MyBP, 3:LyBP 
Median age at CML diagnosis, y (range) 60 (28-86) 46 60.5 (47-66) 
Median follow-up after CML diagnosis, mo (range) 57 (3-109) 55 12.5 (8-40) 
Median time from CML dx to treatment, mo (range) 0.5 (0-2) 0.25 (0-0.5) 
IFN therapy before TKI, no. (%) 3 (33) — — 
TKI as first line (alone or in combination), no. (%) 6 (67) 1 (100) 3 (75), all LBP 
Evolution into AP 1 (11) — — 
Evolution into BP 4 (44) n/a 
Median overall survival, mo (range) 56 (3+ to 109) 55+ 13 (8-40) 
Number surviving 5 (56) 1 (100) 
BCR-ABL/KD mutations at relapse 2* of 7 (29) NA 2 of 2* (100) 

CP indicates chronic phase; AP, accelerated phase; CE, clonal evolution; BP, blast phase; MyBP, myeloid blast phase; LyBP, lymphoid blast phase; PB, peripheral blood; BM, bone marrow; IFN, interferon; TKI, tyrosine kinase inhibitor; KD, kinase domain; dx, diagnosis; mo, months; and —, none.

*

Mutations: E459K in CP patients; V299L and T315I in BP patients.

Ten patients (6 CP, 1 AP, 3 BP) received TKI alone or in combination as their initial therapy (9 imatinib, 1 nilotinib; Table 2). Among patients in CP, 5 received imatinib as frontline therapy and 3 after IFN failure, and after a median follow-up of 37 months (range, 12-72 months), 1 patient (frontline) had no response to imatinib, and the best response for the others was CHR in 4, complete cytogenetic response (CCyR) in 1, and partial cytogenetic response (PCyR) in 2. Notably, only 1 of 5 patients receiving imatinib as frontline therapy achieved CCyR. The patient treated with nilotinib frontline has achieved CCyR after 3 months. None of these patients achieved a major molecular response (MMR), except one who received HCVAD (hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone) with dasatinib after progression to LyBP, achieved CCyR, underwent allogeneic stem cell transplantation (SCT), and has been in complete molecular response (CMR) for 9 months on dasatinib after transplantation. Cytogenetic responses were short lived, lasting a median of 5 months (range, 3-18 months). Five (56%) of the 9 patients in CP (3 receiving frontline TKI therapy) progressed to AP (n = 1) or BP (myeloid n = 3, lymphoid n = 1) after a median of 48 months (range, 4-92 months) and only 1 is alive (after SCT).

Table 2

Response to treatment in CML patients with e1a2 BCR-ABL fusion transcripts

Pt no. Age/ sex CML f/up, mo Frontline
 
1st salvage
 
2nd salvage
 
3rd salvage
 
4th salvage
 
Time to progress, mo CML status 
Rx CML stage Best respon EFS Rx CML stage Best respon EFS Rx CML stage Best respon EFS Rx CML stage Best respon EFS Rx CML stage Best respon EFS 
28/F 108 IFN CP NR IFN + AraC CP CHR Allo CP CCyR IM CP CHR 40 Allo CP NR 89 Died in MyBP 
64/F 109 IFN CP NR HHT + AraC CP CHR IM CP PCyR Nilot AP (CE) PCyR Dasat MyBP NR 92 Died in MyBP 
55/F 85 IFN CP NR IFN + AraC CP NR IM CP CHR 65+ — — — — — — — — — CHR 
79/F 73 IM CP CHR 73+ — — — — — — — — — — — — — — — — — CHR 
35/M 57 IM CP CCyR Dasat AP (CE) CCyR I + A AP NR 2-CdA AP NR AraC + Mitox AP NR 48 Died in AP 
61/F 13 IM CP CHR None MyBP — — — — — — — — — — — — — — 10 Died in MyBP 
38/F 39 IM CP NR — HCVAD + IM LyBP NR MTX + AraC LyBP NR HCVAD + Dasat LyBP CCyR Allo CP (CCyR) CMR 9+ CMR 
60/M 20 IM CP PCyR 18+ — — — — — — — — — — — — — — — — — CHR, PCyR 
86/F Nilot CP CCyR 3+ — — — — — — — — — — — — — — — — — CCyR 
10 46/M 55 IM AP (CE) CHR, no CE 12 Dasat CP (CHR) CHR 27 Bosu CP (CHR) CHR 12+ — — — — — — — — — CHR, CE gone 
11 59/M I + A MyBP NR HD AraC MyBP NR IM MyBP CHR 0.75 — — — — — — — — — Died in MyBP w/ Breast Ca mets 
12 66/M 11 HCVAD + IM LyBP NR IM LyBP CHR 0.25 Clofarabine LyBP CCyR 0.5 IM LyBP NR — — — — — Died in LyBP 
13 47/F 40 HCVAD + IM LyBP CCyR 12 Dasat LyBP CCyR HCVAD LyBP NR Auto LyBP CCyR — — — — — Died in LyBP 
14 62/M 14 IM LyBP NR HCVAD + Dasat LyBP MMR Allo CP, MMR CMR KW-2449 LyBP NR — — — — — Died in LyBP 
Pt no. Age/ sex CML f/up, mo Frontline
 
1st salvage
 
2nd salvage
 
3rd salvage
 
4th salvage
 
Time to progress, mo CML status 
Rx CML stage Best respon EFS Rx CML stage Best respon EFS Rx CML stage Best respon EFS Rx CML stage Best respon EFS Rx CML stage Best respon EFS 
28/F 108 IFN CP NR IFN + AraC CP CHR Allo CP CCyR IM CP CHR 40 Allo CP NR 89 Died in MyBP 
64/F 109 IFN CP NR HHT + AraC CP CHR IM CP PCyR Nilot AP (CE) PCyR Dasat MyBP NR 92 Died in MyBP 
55/F 85 IFN CP NR IFN + AraC CP NR IM CP CHR 65+ — — — — — — — — — CHR 
79/F 73 IM CP CHR 73+ — — — — — — — — — — — — — — — — — CHR 
35/M 57 IM CP CCyR Dasat AP (CE) CCyR I + A AP NR 2-CdA AP NR AraC + Mitox AP NR 48 Died in AP 
61/F 13 IM CP CHR None MyBP — — — — — — — — — — — — — — 10 Died in MyBP 
38/F 39 IM CP NR — HCVAD + IM LyBP NR MTX + AraC LyBP NR HCVAD + Dasat LyBP CCyR Allo CP (CCyR) CMR 9+ CMR 
60/M 20 IM CP PCyR 18+ — — — — — — — — — — — — — — — — — CHR, PCyR 
86/F Nilot CP CCyR 3+ — — — — — — — — — — — — — — — — — CCyR 
10 46/M 55 IM AP (CE) CHR, no CE 12 Dasat CP (CHR) CHR 27 Bosu CP (CHR) CHR 12+ — — — — — — — — — CHR, CE gone 
11 59/M I + A MyBP NR HD AraC MyBP NR IM MyBP CHR 0.75 — — — — — — — — — Died in MyBP w/ Breast Ca mets 
12 66/M 11 HCVAD + IM LyBP NR IM LyBP CHR 0.25 Clofarabine LyBP CCyR 0.5 IM LyBP NR — — — — — Died in LyBP 
13 47/F 40 HCVAD + IM LyBP CCyR 12 Dasat LyBP CCyR HCVAD LyBP NR Auto LyBP CCyR — — — — — Died in LyBP 
14 62/M 14 IM LyBP NR HCVAD + Dasat LyBP MMR Allo CP, MMR CMR KW-2449 LyBP NR — — — — — Died in LyBP 

CP indicates chronic phase; AP, accelerated phase; CE, clonal evolution; BP, blast phase; MyBP, myeloid blast phase; LyBP, lymphoid blast phase; no., number; f/up, follow up; mo, months; Rx, treatment; respon, response; EFS, event-free survival (in months); CHR, complete hematologic response; CCyR, complete cytogenetic response; PCyR, partial cytogenetic response; MCyR, major cytogenetic response; CyR, cytogenetic response; MMR, major molecular response; CMR, complete molecular response; NR, no response; SCT, stem cell transplantation; Allo, allogeneic SCT; Auto, autologous SCT; IFN, interferon; TKI, tyrosine kinase inhibitor; IM, imatinib; Nilot, nilotinib; Dasat, dasatinib; Bosu, bosutinib; I+A, idarubicin + Ara-C (cytarabine); HD AraC, high-dose Ara-C; 2-CdA, 2 chlorodexoyadenosine; Mitox, mitoxantrone; KW-2449, investigational new drug; HCVAD, hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone; MTX, methotrexate; mets, metastasis; and —, none.

Patient 1 received 50 salvage with nilotinib in AP and achieved CHR for 12 months, then received sixth salvage with dasatinib in MyBP and had no response.

The sole patient in AP at diagnosis received imatinib, dasatinib, and bosutinib sequentially, achieving only CHR with each of them. Of the 4 patients with BP at diagnosis, 3 had transient CCyR with HCVAD plus TKI or with clofarabine, but eventually all relapsed and died.

Overall, 6 patients (5 CP, 1 AP) were alive at a median of 39 months (range, 3-85 months) after diagnosis: 3 with CHR (2 on imatinib, 1 bosutinib), 1 with PCyR on imatinib, 1 with CCyR on nilotinib, and 1 with CMR after allogeneic SCT. Median survival was 56 months for patients in CP at the start of therapy, and 13 months for those in BP; the patient in AP has been alive for 55 months.

The e1a2 transcripts may coexist with e13a2(b2a2)/e14a2(b3a2),11  but their expression as the only transcript in CML is rare. P190BCR-ABL is present in 60% to 75% of patients with Ph+ acute lymphoblastic leukemia,19,20  and it can induce rapid transformation of lymphoid progenitor cells.21-23  P190BCR-ABL CML has been reported to have increased monocytosis, with a peripheral blood morphology resembling chronic myelomonocytic leukemia.13  In our study, 4 patients (2 CP, 1 AP, 1 BP) had splenomegaly and 5 (3 CP, 2 BP) had monocytosis. The 3 with CP and monocytosis at presentation continue to be in CP with imatinib treatment, whereas the 2 in BP did not respond to treatment.

Anecdotal reports suggest a poor outcome of patients with P190BCR-ABL CML treated with imatinib2  or other therapies.3-5,11-14  Our analysis demonstrates the poor outcome of these patients despite therapy with TKI. Of the 6 CP patients treated with TKI as initial therapy, 3 transformed to AP or BP and 2 of them died shortly thereafter, whereas the one patient treated with nilotinib as initial therapy has achieved CCyR after 3 months of therapy. In addition, none of the 14 patients reported on our analysis achieved MMR with TKI therapy.

We conclude that although P190BCR-ABL CML represents only 1% of patients with CML, it is associated with an inferior outcome to therapy with TKI, with few, usually short-lived responses. These patients need to be identified as high-risk patients, monitored closely for efficacy during therapy with TKI, and offered SCT early if eligible for this procedure.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Authorship

Contribution: D.V. wrote the paper, analyzed data, and approved the paper; J.C. designed the study, managed the patients, analyzed data, and reviewed and approved the paper; and H.M.K., D.J., R.L., G.B., S.V., and M.B.R. approved the paper and managed the patients.

Conflict-of-interest disclosure: H.M.K. and J.C. have research grants from Novartis and BMS. The remaining authors declare no competing financial interests.

Correspondence: Jorge Cortes, Professor of Medicine, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030; e-mail: jcortes@mdanderson.org.

References

References
1
Quintás-Cardama
A
Cortes
A
Molecular biology of BCR-ABL1-positive chronic myeloid leukemia.
Blood
2009
, vol. 
113
 (pg. 
1619
-
1630
)
2
Andrikovics
H
Nahajevszky
S
Szilvási
A
, et al. 
First and second line imatinib treatment in chronic myelogenous leukemia patients expressing rare e1a2 or e19a2 BCR-ABL transcripts.
Hematol Oncol
2007
, vol. 
25
 (pg. 
143
-
147
)
3
Hur
M
Song
EY
Kang
SH
, et al. 
Lymphoid preponderance and the absence of basophilia and splenomegaly are frequent in m-bcr-positive chronic myelogenous leukemia.
Ann Hematol
2002
, vol. 
81
 (pg. 
219
-
223
)
4
Ohsaka
A
Shiina
S
Kobayashi
M
Kudo
H
Kawaguchi
R
Philadelphia chromosome-positive chronic myeloid leukemia expressing p190(BCR-ABL).
Intern Med
2002
, vol. 
41
 (pg. 
1183
-
1187
)
5
Ravandi
F
Cortes
J
Albitar
M
, et al. 
Chronic myelogenous leukaemia with p185 (BCR/ABL) expression: characteristics and clinical significance.
Br J Haematol
1999
, vol. 
107
 (pg. 
581
-
586
)
6
Verstovsek
S
Lin
H
Kantarjian
H
, et al. 
Neutrophilic-chronic myeloid leukemia: low levels of p230 BCR/ABL mRNA and undetectable BCR/ABL protein may predict an indolent course.
Cancer
2002
, vol. 
94
 (pg. 
2416
-
2425
)
7
Pane
F
Frigeri
F
Sindona
M
, et al. 
Neutrophilic chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with C3/A2 junction).
Blood
1996
, vol. 
88
 (pg. 
2410
-
2414
)
8
Leibundgut
EO
Jotterand
M
Rigamonti
V
, et al. 
A novel BCR-ABL transcript e2a2 in a chronic myelogenous leukaemia patient with a duplicated Ph-chromosome and monosomy 7.
Br J Haematol
1999
, vol. 
106
 (pg. 
1041
-
1044
)
9
Popovici
C
Cailleres
S
David
M
Lafage-Pochitaloff
M
Sainty
D
Mozziconacci
MJ
E6a2 BCR-ABL fusion with BCR exon 5-deleted transcript in a Philadelphia positive CML responsive to Imatinib.
Leuk Lymphoma
2005
, vol. 
46
 (pg. 
1375
-
1377
)
10
Melo
JV
BCR-ABL gene variants.
Baillieres Clin Haematol
1997
, vol. 
10
 (pg. 
203
-
222
)
11
van Rhee
F
Hochhaus
A
Lin
F
Melo
JV
Goldman
JM
Cross
NC
p190 BCR-ABL mRNA is expressed at low levels in p210-positive chronic myeloid and acute lymphoblastic leukemias.
Blood
1996
, vol. 
87
 (pg. 
5213
-
5217
)
12
Selleri
L
von Lindern
M
Hermans
A
Meijer
D
Torelli
G
Grosveld
G
Chronic myeloid leukemia may be associated with several bcr-ab1 transcripts including the acute lymphoid leukemia-type 7 kb transcript.
Blood
1990
, vol. 
75
 (pg. 
1146
-
1153
)
13
Melo
JV
Myint
H
Galton
DA
Goldman
JM
P190BCR-ABL chronic myeloid leukaemia: the missing link with chronic myelomonocytic leukaemia?
Leukemia
1994
, vol. 
8
 (pg. 
208
-
211
)
14
Solves
P
Bolufer
P
López
JA
, et al. 
Chronic myeloid leukemia with expression of ALL-type BCR/ABL transcript: a case-report and review of the literature.
Leuk Res
1999
, vol. 
23
 (pg. 
851
-
854
)
15
Kantarjian
HM
Dixon
D
Keating
MJ
, et al. 
Characteristics of accelerated disease in chronic myelogenous leukemia.
Cancer
1988
, vol. 
61
 (pg. 
1441
-
1446
)
16
Luthra
R
Medeiros
LJ
TaqMan reverse transcriptase-polymerase chain reaction coupled with capillary electrophoresis for quantification and identification of bcr-abl transcript type.
Methods Mol Biol
2006
, vol. 
335
 (pg. 
135
-
145
)
17
Talpaz
M
Silver
RT
Druker
BJ
, et al. 
Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study.
Blood
2002
, vol. 
99
 (pg. 
1928
-
1937
)
18
O'Brien
SG
Guilhot
F
Larson
RA
, et al. 
Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia.
N Engl J Med
2003
, vol. 
348
 (pg. 
994
-
1004
)
19
Cimino
G
Pane
F
Elia
L
, et al. 
The role of BCR/ABL isoforms in the presentation and outcome of patients with Philadelphia-positive acute lymphoblastic leukemia: a seven-year update of the GIMEMA 0496 trial.
Haematologica
2006
, vol. 
91
 (pg. 
377
-
380
)
20
Gleissner
B
Gökbuget
N
Bartram
CR
, et al. 
Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis.
Blood
2002
, vol. 
99
 (pg. 
1536
-
1543
)
21
Li
S
Ilaria
RL
Jr
Million
RP
Daley
GQ
van Etten
RA
The P190, P210, P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity.
J Exp Med
1999
, vol. 
189
 (pg. 
1399
-
1412
)
22
Lugo
TG
Pendergast
AM
Muller
AJ
Witte
ON
Tyrosine kinase activity and transformation potency of bcr-abl oncogene products.
Science
1990
, vol. 
247
 (pg. 
1079
-
1082
)
23
McLaughlin
J
Chianese
E
Witte
ON
Alternative forms of the BCR-ABL oncogene have quantitatively different potencies for stimulation of immature lymphoid cells.
Mol Cell Biol
1989
, vol. 
9
 (pg. 
1866
-
1874
)