Impact of Additional Cytogenetic Abnormalities in Adults with Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

Abstract

The occurrence of additional cytogenetic abnormalities (ACA) is common in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) but is of unknown significance in the tyrosine-kinase inhibitor (TKI) era. We retrospectively analyzed data from a consecutive case series of adults with Ph+ ALL who had undergone allogeneic hematopoietic cell transplantation (alloHCT) at City of Hope between 2003 and 2014. Among 130 adults with Ph+ ALL who had TKI therapy prior to alloHCT, 78 cases had available data on conventional cytogenetics at diagnosis and were eligible for outcomes analysis. ACA was observed in 41 cases (53%). There were no statistically significant differences in median age, median initial white blood count, post-HCT TKI maintenance, or disease status at the time of transplant between the Ph-chromosome only and ACA cohorts; however, the Ph-chromosome only cohort had a higher rate of minimal residual disease (MRD) positivity at the time of HCT. Three-year leukemia-free survival (LFS) [79.8% vs. 39.5%, p=0.01] and 3-year overall survival (OS) [83% vs. 45.6%, p = 0.02] were superior in the Ph chromosome only, compared to ACA cohorts, respectively. Monosomy 7 was the most common additional aberration observed in our ACA cohort (N=12). Thus, when TKI therapy and alloHCT are utilized as part of adult Ph+ ALL therapy, the presence of ACA appears to have a significant deleterious effect on outcomes post HCT.
Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Full text

The impact of additional cytogenetic abnormalities in adults with
Philadelphia chromosome-positive acute lymphoblastic
leukemia undergoing allogeneic hematopoietic cell
transplantation
Ibrahim Aldoss1, Tracey Stiller2, Thai M Cao1, Joycelynne M. Palmer2, Sandra H. Thomas1,
Stephen J. Forman1, and Vinod Pullarkat1
1Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA
2Department of Information Science, City of Hope, Duarte, CA
Abstract
The occurrence of additional cytogenetic abnormalities (ACA) is common in Philadelphia
chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) but is of unknown significance in
the tyrosine-kinase inhibitor (TKI) era. We retrospectively analyzed data from a consecutive case
series of adults with Ph+ ALL who had undergone allogeneic hematopoietic cell transplantation
(alloHCT) at City of Hope between 2003 and 2014. Among 130 adults with Ph+ ALL who had
TKI therapy prior to alloHCT, 78 cases had available data on conventional cytogenetics at
diagnosis and were eligible for outcomes analysis. ACA was observed in 41 cases (53%). There
were no statistically significant differences in median age, median initial white blood count, post-
HCT TKI maintenance, or disease status at the time of transplant between the Ph-chromosome
only and ACA cohorts; however, the Ph-chromosome only cohort had a higher rate of minimal
residual disease (MRD) positivity at the time of HCT. Three-year leukemia-free survival (LFS)
[79.8% vs. 39.5%, p=0.01] and 3-year overall survival (OS) [83% vs. 45.6%, p = 0.02] were
superior in the Ph chromosome only, compared to ACA cohorts, respectively. Monosomy 7 was
the most common additional aberration observed in our ACA cohort (N=12). Thus, when TKI
therapy and alloHCT are utilized as part of adult Ph+ ALL therapy, the presence of ACA appears
to have a significant deleterious effect on outcomes post HCT.
Keywords
Philadelphia-chromosome positive; Ph+; additional cytogenetic abnormalities; monosomy 7;
allogeneic; stem cell transplant
Corresponding author: Ibrahim Aldoss, MD, Department of Hematology and Hematopoietic Cell Transplantation, 1500 E. Duarte
Road, Duarte, CA 91010-3000, Phone: 626-256-4673, Ext. 62405, Fax: 626-301-8116, ialdoss@coh.org.
Conflict of interest statement: None of the authors has conflicts of interest to declare.
HHS Public Access
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Biol Blood Marrow Transplant. Author manuscript; available in PMC 2016 July 01.
Published in final edited form as:
Biol Blood Marrow Transplant. 2015 July ; 21(7): 1326–1329. doi:10.1016/j.bbmt.2015.03.021.
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Introduction
Philadelphia chromosome (Ph) is the most common cytogenetic abnormality in adults with
acute lymphoblastic leukemia (ALL) [1, 2]. The presence of Ph chromosome has long been
considered an adverse prognostic feature and was associated with dismal outcomes in the
pre-tyrosine kinase inhibitor (TKI) era. For patients with Ph+ ALL treated with
chemotherapy alone, complete remission (CR) rates were low and leukemia relapse was the
norm in the absence of allogeneic hematopoietic stem cell transplantation (alloHCT) [3–6].
Therefore, alloHCT was routinely recommended for eligible patients with available donors.
However, the introduction of TKIs has drastically improved the outcome of Ph+ ALL, and
currently, remission is achieved in the majority of cases [7, 8]. Nonetheless, alloHCT
continues to be the preferred consolidation therapy in adults with Ph+ ALL due to lack of
long-term data on patients treated with combination chemotherapy and TKIs without
alloHCT.
Although additional cytogenetic abnormalities (ACA) at diagnosis are detected in
approximately two thirds of cases with Ph+ ALL [5, 9–11], its prognostic significance in
patients who are treated with TKI and alloHCT remains unclear. In this study, we
investigated the prognostic implications of ACA in adults with Ph+ ALL who had received
TKI therapy prior to consolidation with alloHCT.
Methods
We reviewed all cases of adult Ph+ ALL who had undergone alloHCT at City of Hope
Medical Center between 01/2003 and 04/2014. Only patients with available conventional
cytogenetic documentation of the Ph chromosome with an adequate number of analyzed
metaphases (≥ 20) were included in the outcomes analysis. We excluded patients younger
than 18 years of age and patients who did not receive pre-transplant TKI-based therapy.
Statistical analysis
Demographic, disease and treatment characteristics were summarized using descriptive
statistics. The Wilcoxon Rank Sum test and Chi-sqaure test were used to determine
differences in demographic and disease characteristics of interest. Survival estimates were
calculated using the Kaplan-Meier product-limit method [12] and confidence intervals were
calculated using the logit transformation and the Greenwood variance estimate [13].
Differences between Kaplan-Meier curves were determined using the log-rank test. Overall
survival (OS) was defined as time from date of transplant to death from any cause.
Leukemia-free survival (LFS) was measured as time from date of transplant to relapse or
death from any cause, whichever occurred first. Patients who were alive at the time of
analysis were censored at the last contact date.
Prognostic variables analyzed included patient age at transplant, initial white blood cell
count (WBC), disease status at transplant (CR1 versus beyond CR1), and cytogenetic risk
(isolated versus ACA, and isolated versus ACA with −7, versus ACA without −7). All
analyses were performed using SAS v09.3 (SAS Institute, Cary, NC). The data were locked
for analysis August 5, 2014.
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Results
We identified 134 consecutive adults with Ph+ ALL who had undergone alloHCT during the
selected time period. Five cases were excluded due to the lack of pretransplant TKI therapy.
Fifty-one cases with Ph positivity demonstrated only by PCR and/or FISH for BCR-ABL
were excluded due to unavailability of conventional cytogenetics [n=28], no growth/
insufficient growth [n=12], or karyotyping that did not show t(9;22)(q34.1;q11.2) [n=11]).
Patient and disease characteristics are shown in Table 1.
Among the 78 cases who met the eligibility criteria, 41 (53%) had ACA and 37 had isolated
t(9;22). There were 4 cases of ≥3-way complex BCR-ABL1 translocations (variant
translocations with one or more chromosomes involved in addition to 9 and 22) involving
chromosomes 6, 7, 10, 14 and 19, of which 3 cases were in the isolated Ph+ subgroup and 1
case was in the ACA subgroup. The median age was 41.4 years (19.8–68.4). Forty-nine of
the patients (63%) were male. Donors were matched siblings in 35 patients (45%). The
source of stem cells was peripheral blood in 65 patients (83%). The conditioning regimen
was myeloablative in 59 patients (76%). Tacrolimus/sirolimus-based GVHD prophylaxis
was the most commonly used conditioning regimen, in 59 patients (76%). Patient disease
and transplant characteristics are shown in Table 1.
Monosomy 7 (−7) was the most commonly observed ACA (29%, N =12) and was the only
ACA in 8 cases. The second most common abnormality was derivative chromosome 22 (N =
9). There were 6 cases of hyperdiploidy (> 50 chromosomes) in the ACA cohort. The most
common trisomies were 6, 8 and 21, seen in 5, 8 and 5 cases, respectively. Most trisomies
were part of other additional cytogenetic abnormalities. Excluding cases with −7, there were
8 cases that met the definition of monosomal karyotype (2 autosomal monosomies or 1
monosomy combined with structural aberration). There was one case of concurrent
occurrence of mixed myeloid leukemia (MLL) and Ph+ rearrangements. Cytogenetic
abnormalities are summarized in Table 1. There was no difference in median age (p=0.08),
median initial WBC (p=0.99), disease status at the time of transplant (p=0.58), or post-HCT
TKI maintenance therapy (p=0.93), between the isolated Ph-chromosome and ACA cohorts.
However, more patients with Philadelphia-chromosome alone had minimal residual disease
(MRD) positivity (based on BCR/ABL by PCR) prior to HCT compared to patients with
ACA (p=0.0088), as seen in Table 1. The median follow-up for surviving patients from the
time of transplant was 43 months (range: 4.1–133 months) and 47 months (range: 3.2–123
months) for isolated t(9;22) and ACA cohorts, respectively. Five (14%) patients relapsed in
the isolated t(9;22) group and eight (20%) relapsed in the ACA group. One-year non-relapse
mortality (NRM) for the whole cohort was 20%. The 3-year OS of 45.6% (95% CI: 28.2–
61.5) in the ACA group was significantly worse than the 83% (95% CI: 65.9–92.0) seen in
the isolated Ph chromosome group (p =0.02). Likewise, the 3-year LFS of 39.5% (95% CI:
23.3–55.3) for ACA was significantly worse than the 79.8% (95% CI: 62.2–89.9) in the
isolated Ph+ group (p=0.01) (Figure 1). No multivariate analysis was performed given the
small study size and the fact that no significant differences in OS or LFS were seen in
univariate analysis other than the presence of ACA. The 3-year OS and LFS for the 51 Ph+
patients excluded from the analysis were 53.9% and 38.6%, respectively.
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Since monosomy 7 was the most common ACA, we examined its impact on HCT outcomes
by splitting the Ph+ cohort into three subgroups: isolated Ph chromosome, Ph+ with − 7, and
Ph+ with other ACA. Both 3-year OS and LFS were inferior in patients with Ph+ and other
ACA (non-7) compared to isolated Ph+ and Ph+ with −7 cohorts (Figure 2). Three-year OS
for Ph+ (other ACA) was 39.7% (95%CI: 20.3–58.6) vs. 83.0% (95%CI: 65.9–92.0) for Ph+
(alone) vs. 59.7% (95%CI: 24.1–82.9) for Ph+ (with −7), (p=0.01). Three-year LFS was
30.2% (95%CI: 13.3–49.0) for Ph+ (other ACA) vs. 79.8% (95%CI: 62.2–89.9) for Ph+
(alone) vs. 60.6% (95%CI: 25.8–83.1) Ph+ (with −7), (p=0.001)
Discussion
Our study is unique in that it examines the impact of ACA in Ph+ patients treated with TKIs
and consolidated with alloHCT, and therefore, it is relevant to contemporary management of
Ph+ALL compared to previous reports examining this issue [5, 9].
Additional cytogenetic abnormalities (ACA) occur frequently in Ph+ ALL, and have been
reported in over 60% of cases [5, 9–11]. Additional aberrations involving chromosomes 8, 7,
9, 21 and 22 were most commonly reported [9, 10]. In the pre-TKI era, two studies
investigated the prognostic significance of ACA in Ph+ ALL. The first study included 249
children with Ph+ ALL from 10 large pediatric groups diagnosed between 1986 and 1996.
Patients were treated with different regimens and only 67 patients (27%) underwent
alloHCT as part of their ALL treatment. Event free survival (EFS) and overall survival (OS)
were lower in patients with ACA and loss of chromosome 7, 7p, and/or 9p, but the inferior
outcome was not significant when adjusted to other prognostic factors [5]. The second
analysis included 111 adults with Ph+ ALL who were treated in one of 7 different CALGB
studies between 1985 and 2000. Only 24 patients (22%) underwent alloHCT. Monosomy 7
was associated with a lower CR rate, and complex cytogenetics (≥ 3 abnormalities) was
associated with higher CR rate. The presence of +der(22)t(9;22) was associated with higher
risk of relapse [9]. However, these previous two studies included patients who did not
receive TKIs as part of ALL therapy, and alloHCT was only utilized in approximately a
quarter of the cases.
Our analysis shows inferior LFS and OS in patients with Ph+ ALL with ACA compared to
those with isolated t(9;22) despite a higher rate of pre-HCT MRD positivity in the latter
group. Monosomy 7 was the most common additional abnormality in our cohort and usually
occurred as an isolated extra finding. The inferior outcome of ACA cohort was more
pronounced in patients without monosomy 7 compared to those with monosomy 7. The
basis for the worse LFS in the ACA group without monosomy 7 remains unclear and may be
related to the specific nature of the more prevalent abnormalities in this group. The small
number of cases makes it difficult to draw firm conclusions regarding this observation.
In conclusion, the presence of ACA, especially in patients without monosomy 7, appears to
adversely impact the post-transplant outcomes in Ph+ALL when TKI and alloHCT are
utilized as part of the treatment program. Due to their poor outcomes, these patients are
probably best served if treated in the context of a clinical trial. We believe this data supports
further investigation in an unbiased prospective dataset, which might identify a higher risk
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group of Ph+ ALL who could benefit from additional treatment such as post-transplant
maintenance TKI therapy to reduce relapse risk.
Acknowledgments
This work was partially supported by the City of Hope Comprehensive Cancer Center support grant NCI CA33572.
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Highlights
•Additional cytogenetic abnormalities (ACA) are common in Ph+ ALL
•Monosomy 7 was the most common ACA in our cohort
•When TKI therapy and allogeneic HCT were utilized as part of adult Ph+ ALL
therapy, the presence of ACA appeared to have a significant deleterious effect
on outcomes
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Figure 1. Survival outcomes stratified by presence/absence of ACA
Panel A plots overall survival (OS) and Panel B plots leukemia-free survival (LFS) by
Kaplan-Meier. Solid lines represent patients with isolated Ph+ (n=37), and dashed lines
represent patients with Ph+ and additional cytogenetic abnormalities (ACA) (n=41).
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Figure 2. Survival outcomes stratified by presence/absence of monosomy 7 and other ACA
Panel A plots overall survival (OS) and Panel B plots leukemia-free survival (LFS) by
Kaplan-Meier. Solid black lines represent patients with isolated Ph+ (n=37), solid grey lines
represent patients with Ph+ and monosomy 7 (n=12), and dashed lines represent patients
with Ph+ and non-monosomy 7 additional cytogenetic abnormalities (ACA) (n=29).
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Table 1
Patient, disease, and treatment characteristics
Variables
No t(9;22)
Cytogenetics*
(N=51)
Isolated Ph+
Cytogenetics
(N=37)
Ph+ plus
ACA
(N=41)
Age (yrs) 44.3 (18.9–68.5) 49 (19.8–68.4) 38.6 (21.4–61.0)
Gender
Female 22 (43) 17 (46) 13 (32)
Male 29 (57) 20 (54) 28 (68)
WBC 18.2 (1.2–425) 37.1 (1.1–440.0) 22.6 (1.2–426.0)
Disease Status
CR1 37 (73) 31 (84) 34 (83)
CR2 or beyond 10 (20) 3 (8) 4 (10)
Active disease at HCT 4 (8) 3 (8) 3 (7)
Cytogenetic Remission** 40/41 (98) 26/29 (90) 29/33 (88)
MRD Status Pre-HCT
MRD positive 14 (27) 17 (46) 9 (22)
MRD negative 28 (55) 13 (35) 27 (66)
Unknown 9 (18) 7 (19) 5 (12)
Time from Diagnosis to Transplant (days) 210 (75–1748) 135 (71–434) 177 (68–1,162)
Pre-HCT TKI
Imatinib 35 (67) 23 (62) 29 (71)
Dasatinib 11 (23) 11 (30) 7 (17)
Imatinib/Dasatinib 5 (10) 3 (8) 5 (12)
Post-HCT TKI Maintenance
Yes 18 (35) 19 (51) 21 (51)
No 30 (59) 16 (43) 17 (41)
Not Applicable#3 (6) 2 (5) 3 (7)
Donor Type
Sibling 29 (57) 16 (43) 19 (46)
Unrelated 22 (43) 21 (57) 22 (54)
Stem Cell Source
Bone Marrow 3 (6) 2 (5) 6 (15)
Cord Blood/Double Cord 4 (8) 0 (0) 6 (15)
Peripheral Blood 44 (86) 35 (95) 29 (71)
Conditioning Regimen Intensity
RIC/NMA 14 (27) 11 (30) 9 (22)
MAC 37 (73) 26 (70) 32 (78)
Conditioning Regimens
FTBI/Etoposoide 29 (57) 25 (68) 27 (66)
Fludarabine/Melphalan 15 (29) 10 (27) 6 (15)
Cytoxan/Fludarabine/TBI 7 (14) 0 (0) 6 (15)
Others 0 (0) 2 (5) 2 (5)
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Aldoss et al. Page 10
Variables
No t(9;22)
Cytogenetics*
(N=51)
Isolated Ph+
Cytogenetics
(N=37)
Ph+ plus
ACA
(N=41)
Cytogenetic abnormalities
Ph+ by FISH or PCR only 51 (100) 0
Ph+ by conventional cytogenetics 0 37 (10) 41 (10)
−7 NA 0 12
−8, i(8) or +8 NA 0 11
9p del, −9, der(9), add(9p) or +9 NA 0 11
der(22) NA 0 9
Monosomy, excluding −7 NA 0 8
Hyperdiploidy NA 0 6
*By conventional cytogenetics
**Patients in CR1 or CR2 with available cytogenetics (denominator) who were also in cytogenetic remission (numerator)
#Death within 60 days of HCT
Ph+ – Philadelphia Chromosome positive, ACA – additional cytogenetic abnormalities, RIC – reduced intensity conditioning, NMA – non-
myeloablative, MAC – myeloablative conditioning, WBC – white blood cell count, CR1
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