Written in Blood
BCR-ABL Transcript Type Predicts Response and Survival Among Patients
with CML
The presence of one or both of the most common BCR-ABL transcripts
in patients with chronic-phase chronic myeloid leukemia (CML), e13a2
and e14a2, is predictive of response to tyrosine kinase inhibitors (TKIs)
and longer survival, according to results from a recent report in Blood.
“We have always considered the two variants of the typical BCR-ABL
translocation as being equivalent in clinical features and outcome,” Preetesh Jain, MD, lead author of the study, told ASH Clinical News. “Our
results suggest that the outcome may not be equal, with patients with
e14a2 having a better probability of response.”
Dr. Jain and colleagues at the University of Texas MD Anderson Cancer Center in Houston, examined BCR-ABL transcripts in 487 patients
with chronic-phase CML who were treated with TKIs between July 2000
and September 2013. Patients were treated with one of four different
frontline TKI modalities:
Cytogenetic and Molecular Response Rates
e13a2
e14a2
Both e13a2/e14a2
Complete cytogenetic response
Three months
59%
67%
63%
Six months
73%
81%
82%
• Imatinib 800 mg daily (n=199)
Major molecular response
• Nilotinib 400 mg twice daily (n=108)
The researchers measured event-free survival (EFS) from the start of
treatment until any of the following eve nts occurred: loss of complete
hematologic remission, loss of major cytogenetic response, progression
to accelerated or blast phase, or death from any cause.
Overall survival (OS) and transformation-free survival (TFS) were
also measured. Cytogenetic analysis was conducted every three months
for the first year, every six months for the subsequent two to three years,
and every one to two years thereafter.
Nearly all patients (481 out of 487) expressed e13a2, e14a2, or both
transcripts:
• e13a2: 200 (42%)
• e14a2: 196 (41%)
• both transcripts: 85 (18%)
Baseline characteristics were similar among patients treated with the different TKI modalities, though patients with e13a2 had significantly lower
platelets compared with those with e14a2 or both transcripts (p<0.001).
Twenty-one patients (4%) experienced disease evolution, and
14 patients (3%) died during the
study follow-up. Of the patients
whose disease evolved to accelerated phase or blast crisis CML,
15 expressed e13a2 (8% of all
patients with this expression) and
six expressed e14a2 (3% of all patients with this expression), while
none of these patients expressed
both transcripts (p=0.04).
Patients with e13a2 transcripts experienced lower rates
of major molecular response
(MMR) and complete cytogenetic response (CCyR) compared
with patients who expressed
e14a2 or both transcripts. The
rates of response at three and six
months are reported in TABLE 1.
—PREETESH JAIN, MD
In multivariate analyses, the
expression of e14a2 or both transcripts were independent predic-
“Transcript
type could be
a tool to help
select the TKI
to be used for
patients with
newly diagnosed CML.”
ASH Clinical News
TABLE 1.
• Imatinib 400 mg daily (n=69)
• Dasatinib 50 mg twice daily or 100 mg daily (n=105)
32
tors of optimal responses, as well as longer EFS (p=0.043 for e14a2) and
TFS (p=0.04 for both). They did not, however, predict for better OS.
“One possible explanation for inferior outcome for patients with
e13a2 is the reported higher tyrosine kinase activity reflected by higher
pCrKL levels with e13a2 transcripts,” Dr. Jain and co-authors explained,
“which could result in a given TKI being able to more effectively suppress
the kinase activity associated with the less active e14a2 transcripts.”
The type of TKI treatments patients received could also explain the
differences in response and survival, the authors noted.
Three months
27%
49%
50%
Six months
42%
67%
70%
“Interestingly, there was a suggestion that treatment with imatinib
400 mg daily was associated with a lower probability of response only
among patients with e13a2,” they reported. In addition, the rates of CCyR
and MMR for patients with e14a2 or with co-expression of e13a2 and
e14a2 treated with imatinib 400 mg daily was similar to that of patients
treated with imatinib 800 mg, dasatinib, or nilotinib. “If these observations were to be confirmed in a prospective study, it would suggest
that transcript type could be a tool to help select the TKI to be used for
patients with newly diagnosed CML.”
For example, Dr. Jain explained, patients with e14a2 could be offered
imatinib 400, whereas those with e13a2 may derive more benefit from
the use of second-generation TKI as initial therapy. “The study results
need to be validated prospectively, but this could provide an additional
biomarker that can help guide therapy in different circumstances,” he
added.
Limitations of the study include its retrospective, non-controlled
design, as well as that the study cannot be generalized to different
institutions. ●
REFERENCE
Jain P, Kantarjian H, Patel KP, et al. Impact of BCR-ABL transcript type on response and survival in patients with chronic
phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood. 2016 January 4. [Epub ahead of print]
Study Finds GATA2 Deficiency
Predisposes Children to MDS
Germline GATA2 mutations account for 15 percent of advanced
and 7 percent of primary cases
of myelodysplastic syndromes
(MDS) in pediatric patients, but
their presence does not affect rates
of overall survival, according to
research recently published in
Blood.1 In this study of children
and adolescents with MDS, the
authors, led by Marcin W. Wlodarski, MD, also found that the
majority of patients (72%) who
had the cytogenetic aberration
monosomy 7 carried an underlying GATA2 deficiency.
“Significant differences between primary MDS in children
and adults are evident for morphology, cytogenetics, therapeutic
approaches, and the somatic mutation landscape,” Dr. Wlodarski,
from the Department of Pediatrics
and Adolescent Medicine in the
Division of Pediatric Hematology
and Oncology at the University
of Freiburg in Germany, and colleagues wrote. The role of GATA2
mutations in this disease is not
well understood, limiting clinicians’ ability to predict outcomes
and make recommendations for
February 2016