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Regular Article
CLINICAL TRIALS AND OBSERVATIONS
Nilotinib combined with multiagent chemotherapy for newly diagnosed
Philadelphia-positive acute lymphoblastic leukemia
Dae-Young Kim,1 Young-Don Joo,2 Sung-Nam Lim,2 Sung-Doo Kim,1 Jung-Hee Lee,1 Je-Hwan Lee,1
Dong Hwan (Dennis) Kim,3 Kihyun Kim,3 Chul Won Jung,3 Inho Kim,4 Sung-Soo Yoon,4 Seonyang Park,4 Jae-Sook Ahn,5
Deok-Hwan Yang,5 Je-Jung Lee,5 Ho-Sup Lee,6 Yang Soo Kim,6 Yeung-Chul Mun,7 Hawk Kim,8 Jae Hoo Park,8
Joon Ho Moon,9 Sang Kyun Sohn,9 Sang Min Lee,10 Won Sik Lee,10 Kyoung Ha Kim,11 Jong-Ho Won,11 Myung Soo Hyun,12
Jinny Park,13 Jae Hoon Lee,13 Ho-Jin Shin,14 Joo-Seop Chung,14 Hyewon Lee,15 Hyeon-Seok Eom,15 Gyeong Won Lee,16
Young-Uk Cho,17 Seongsoo Jang,17 Chan-Jeoung Park,17 Hyun-Sook Chi,17 and Kyoo-Hyung Lee,1 for the Adult Acute
Lymphoblastic Leukemia Working Party of the Korean Society of Hematology
1
Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 2Department of Internal Medicine, Haeundae Paik
Hospital, College of Medicine Inje University, Busan, Korea; 3Division of Hematology/Oncology, Department of Medicine, Sungkyunkwan University School
of Medicine, Samsung Medical Center, Seoul, Korea; 4Division of Hematology-Medical Oncology, Department of Internal Medicine, Cancer Research
Institute, Seoul National University College of Medicine, Seoul, Korea; 5Department of Hematology and Oncology, Chonnam National University Hwasun
Hospital, Jeollanam-do, Korea; 6Division of Hematology/Oncology, Department of Internal Medicine, Kosin University College of Medicine, Kosin University
Gospel Hospital, Busan, Korea; 7Division of Hematology-Oncology, Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul,
Korea; 8Division of Hematology and Cellular Therapy, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea; 9Department of
Hematology/Oncology, Kyungpook National University Hospital, Daegu, Korea; 10Department of Hemato-Oncology, Inje University Busan Paik Hospital,
Busan, Korea; 11Division of Hematology-Oncology, Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University
College of Medicine, Seoul, Korea; 12Division of Hematology-Oncology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu,
Korea; 13Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea; 14Department of Hematology-Oncology, School of
Medicine, Pusan National University Hospital Medical Research Institute, Busan, Korea; 15Hematologic Oncology Clinic, Center for Specific Organs Center,
National Cancer Center, Goyang, Korea; 16Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Hospital,
Gyeongsang National University School of Medicine, Jinju, Korea; and 17Department of Laboratory Medicine, Asan Medical Center, University of Ulsan
College of Medicine, Seoul, Korea
We investigated the effects of nilotinib plus multiagent chemotherapy, followed by
consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for
adult patients with newly diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic
• Nilotinib plus multiagent
leukemia (ALL). Study subjects received induction treatment that comprised concurrent
chemotherapy was feasible
vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic
and showed a comparable
remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year
outcome to previous results
maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at
with imatinib for Ph-pos ALL.
HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for
• The achievement of deep MR
BCR-ABL1/G6PDH ratios £1023 and MR5 for ratios <1025. Ninety evaluable subjects, ages
with nilotinib at postremission 17 to 71 years, were enrolled in 17 centers. The HCR rate was 91%; 57 subjects received
correlated well with the clinical allo-HCT. The cumulative MR5 rate was 94%; the 2-year hematologic relapse-free survival
outcomes for Ph-pos ALL.
(HRFS) rate was 72% for 82 subjects that achieved HCR, and the 2-year overall survival
rate was 72%. Subjects that failed to achieve MR3 or MR5 were 9.1 times (P 5 .004) or 6.3
times (P 5 .001) more prone to hematologic relapse, respectively, than those that achieved MR3 or MR5. MRD statuses just before alloHCT and at 3 months after allo-HCT were predictive of 2-year HRFS. Adverse events occurred mainly during induction, and most were
reversible with dose reduction or transient interruption of nilotinib. The combination of nilotinib with high-dose cytotoxic drugs was
feasible, and it effectively achieved high cumulative complete molecular remission and HRFS rates. The MRD status at early postremission
time was predictive of the HRFS. This trial was registered at www.clinicaltrials.gov as #NCT00844298. (Blood. 2015;126(6):746-756)
Key Points
Introduction
BCR-ABL1 tyrosine kinase inhibitors (TKIs) are considered an important component of treatment of Philadelphia-positive (Ph-pos) acute
lymphoblastic leukemia (ALL). Recent studies reported that treating
Ph-pos ALL with the combination of imatinib and multiagent chemo-
therapy improved the overall outcome.1,2 Based on improvements in
efficacy and tolerability, next-generation TKIs have been widely used
in first-line treatments for chronic myeloid leukemia (CML),3,4 and
dasatinib is used in second-line treatments for patients with Ph-pos
Submitted March 23, 2015; accepted June 5, 2015. Prepublished online as
Blood First Edition paper, June 11, 2015; DOI 10.1182/blood-2015-03636548.
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.
The online version of this article contains a data supplement.
© 2015 by The American Society of Hematology
746
BLOOD, 6 AUGUST 2015 x VOLUME 126, NUMBER 6
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BLOOD, 6 AUGUST 2015 x VOLUME 126, NUMBER 6
ALL that failed to respond or were intolerant to imatinib5 or another
first-line agent.6
Nilotinib is a TKI with a potent binding affinity for BCR-ABL1
tyrosine kinase.7,8 Nilotinib achieved significantly higher molecular response (MR) rates at 24 months9 than imatinib in a phase 3
randomized study for patients with chronic-phase CML. This outcome
in CML suggested that nilotinib may show improved clinical efficacy
for treating Ph-pos ALL compared with imatinib. The adverse event
(AE) profile of nilotinib was different from that of imatinib. Emesis
and diarrhea, which may impede drug compliance with oral agents,
were relatively low with nilotinib; this feature may prove beneficial
when combined with cytotoxic chemotherapeutic agents, which can
aggravate AEs. However, serious AEs may be of concern (eg, hepatic
abnormalities, pancreatitis, and cardiac corrected QT interval prolongation occurred in previous trials of nilotinib treatment of CML).
The present multicenter, phase 2, single arm, prospective study
evaluated the feasibility, efficacy, and safety of combining nilotinib
with multiagent chemotherapy for treating adult patients with Ph-pos
ALL during chemotherapy and during allogeneic hematopoietic cell
transplantation (allo-HCT).
NILOTINIB-BASED CHEMOTHERAPY FOR PH-POSITIVE ALL
747
Table 1. Details of induction/consolidation chemotherapy
Therapy
Induction
Details
Daunorubicin 90 mg/m2 per day; continuous IV
infusion for 24 h, on days 1-3
Vincristine 2 mg, IV push on days 1 and 8
Prednisolone 60 mg/m2 per day p.o., or 48 mg/m2
per day IV, on days 1-14
Nilotinib 400 mg p.o. twice daily (from day 8 to the
start of conditioning for allo-HCT or until the end
of 2 y of maintenance therapy)
Consolidation A (cycle 1)
Daunorubicin 45 mg/m2 per day; continuous IV for
24 h on days 1 and 2
Vincristine 2 mg IV, on days 1 and 8
Prednisolone 60 mg/m2 per day p.o., on days 1-14
Nilotinib 400 mg p.o. twice daily
Consolidation B (cycles 2,4)
Cytarabine 2000 mg/m2 per day IV for 2 h on
days 1-4
Etoposide 150 mg/m2 per day IV for 3 h on
days 1-4
Nilotinib 400 mg p.o. twice daily
Consolidation C (cycles 3,5)
Methotrexate 220 mg/m2 IV bolus, then 60 mg/m2
per hour for 36 h on days 1-2 and 15-16
Leucovorin, followed immediately by 50 mg/m2 IV
every 6 h for 3 doses; then leucovorin p.o. until
serum methotrexate ,0.05 mmol/L
Patients and methods
Patient eligibility
Patients were considered for enrollment when they were aged 15 years or
more, were newly diagnosed with ALL or biphenotypic acute leukemia, and
carried the Philadelphia chromosome (Ph-pos). The Ph-pos status was
detected with the conventional G band by trypsin using the Leishman Giemsa
band technique, and/or the BCR-ABL1 fusion transcript was detected with
a nested reverse-transcription polymerase chain reaction. For study inclusion,
subjects had to demonstrate adequate organ functions (serum creatinine,
,1.5 mg/dL; serum bilirubin, ,1.5 mg/dL; and serum transaminase, ,3
times the upper normal limit or ,5 times the upper normal limit for subjects
with leukemia with hepatic involvement), and subjects had to demonstrate
adequate performance (Eastern Cooperative Oncology Group performance
status10 #2 or Karnofsky scale11 .60%). The institutional review boards
of all participating institutions approved this study. All subjects provided
written informed consent before enrollment, according to the guidelines at
each institution’s Committee on Human Research. This trial was registered at
www.clinicaltrials.gov as #NCT00844298.
Induction and postremission treatment
All subjects received induction chemotherapy, which comprised vincristine,
daunorubicin, and prednisolone (Table 1). Nilotinib was started on the eighth day
of induction therapy at a dose of 400 mg, twice a day.
After achieving hematologic complete remission (HCR), subjects received
5 cycles of consolidation (Table 1) or were considered for allo-HCT. The
criteria were that allo-HCT had to be feasible, a suitable donor was available,
and the subject was willing to receive allo-HCT. Acceptable donors included
matched sibling donors, fully matched or partially matched unrelated donors
(MUDs), and haploidentical familial (familial mismatched) donors. Partially
MUDs were acceptable when no more than 2 mismatches in HLA alleles were
present between the donor and recipient of the allo-HCT. Conditioning for
allo-HCT was at the discretion of each investigator. Stem cells were collected
either from BM or from granulocyte colony-stimulating factor–mobilized
peripheral blood (PB). Prophylaxis for graft-versus-host disease (GVHD)
and prophylactic antibacterial/antifungal/antiviral agents were all given at
the discretion of each investigator. Autologous HCT (auto-HCT) was not
permitted for postremission therapy in this study. Up to 10 intrathecal injections
of methotrexate were given during induction/consolidation therapy as a prophylactic for relapse in the CNS. Whole brain irradiation was not permitted for CNS
prophylaxis.
Nilotinib 400 mg p.o. twice daily
Maintenance
Nilotinib 400 mg p.o. twice daily for 2 y
CNS prophylaxis
Up to 10 doses of intrathecal methotrexate (15 mg)
with hydrocortisone (50 mg) during or after
induction therapy
CNS, central nervous system; p.o., by mouth.
Administration of nilotinib
Nilotinib was introduced concurrent with cytotoxic drugs, starting on the
eighth day of induction therapy, and it was continued up to the start of alloHCT conditioning or until the end of consolidation therapy. Subjects that
proceeded to allo-HCT did not receive nilotinib after allo-HCT. Subjects that
completed 5 cycles of consolidation received 2 years of nilotinib maintenance.
Nilotinib was started at a daily dose of 400 mg twice daily, and it was tapered to
400 mg daily temporarily, when the subject experienced a greater than or equal
to grade 3, nonhematologic AE. The low nilotinib dose was continued until the
AE improved to grade 1. However, nilotinib was discontinued permanently, at
the discretion of each investigator, when severe AEs recurred, despite a dose
reduction. These subjects continued to receive other cytotoxic drugs, and when
desired, they were allowed to remain in the present study.
Assessment of minimal residual disease
Minimal residual disease (MRD) was monitored at the central laboratory of
the Department of Laboratory Medicine, Asan Medical Center, Seoul, Korea.
PB (5 mL) was collected from each subject every 3 months from the time of
achieving HCR until the end of maintenance therapy. For subjects that received
allo-HCT, MRD was evaluated within 1 month prior to the beginning of
conditioning and every 3 months thereafter.
BCR-ABL1 expression was measured with real-time quantitative polymerase chain reaction with the LightCycler-t(9;22) Quantification Kit (Roche
Diagnostics, Basel, Switzerland). Briefly, total RNA was extracted from
leukocytes with the High Pure RNA Isolation Kit (Roche Diagnostics);
complementary DNA was prepared from purified messenger RNA according
to the manufacturer’s instructions. Glucose-6-phosphate dehydrogenase
(G6PDH) served as a control. Amplified BCR-ABL1 and G6PDH products
were compared with standard curves to determine relative concentrations.
The sensitivity of this assay was 1025.
Complete molecular remission (MCR), or a negative MRD, was assumed
when the BCR-ABL1/G6PDH ratio was ,1 3 1025 (MR5). A major MR (MR3)
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BLOOD, 6 AUGUST 2015 x VOLUME 126, NUMBER 6
KIM et al
Table 2. Baseline characteristics of all analyzable subjects
Characteristics
Total (n 5 90)
Age in years, median (range)
47.0 (17-71)
Allo-HCT recipients
(n 5 57)
Allo-HCT nonrecipients
(n 5 25)
P
47.0 (19-61)
57.0 (19-71)
.066
45:45 (50:50)
28:29 (49:51)
11:14 (44:56)
.669
Splenomegaly, n (%)
26 (29)
17 (30)
7 (28)
.867
Extramedullary involvement, n (%)
.536
Number of subjects
,35 vs $35 y
17 vs 73
,45 vs $45 y
38 vs 52
,55 vs $55 y
Male:female, n:n (%:%)
65 vs 25
16 (18)
12 (21)
3 (12)
Cerebrospinal fluid, n (%)
8 (9)
4 (7)
3 (12)
Others,* n (%)
8 (9)
8 (14)
0
Hemogram, PB
WBC (3103/mL), median (range)
25.7 (0.2-547.1)
20.3 (0.2-379.4)
51.1 (1.6-547.1)
.134
% Blast, median (range)
59.0 (0-97.0)
49.0 (0-97.0)
73.0 (0-97.0)
.051
0.8 (0.5-1.5)
.834
Serum laboratory results
Creatinine, mg/dL, median (range)
LDH, IU, median (range)
0.8 (0.3-1.5)
696.0 (116.0-5468.0)
0.8 (0.4-1.5)
716.0 (116.0-5468.0)
786.0 (269.0-3172.0)
Immunologic phenotype
ALL, n (%)
83 (92)
52 (91)
23 (92)
7 (8)
5 (9)
2 (8)
Ph alone, n (%)
30 (33)
17 (30)
10 (40)
Additional type, n (%)
Biphenotypic acute leukemia, n (%)
.841
1.000
Chromosome type
.652
44 (49)
28 (49)
12 (48)
Others, n (%)
6 (7)
5 (9)
1 (4)
No mitosis, n (%)
7 (8)
5 (9)
1 (4)
Unknown, n (%)
3 (3)
2 (4)
1 (4)
Major, n (%)
25 (28)
12 (21)
7 (28)
Minor, n (%)
65 (72)
45 (79)
18 (72)
BCR-ABL1 transcript type
.492
LDH, lactate dehydrogenase; Ph, Philadelphia; WBC, white blood cell.
*Skin (n 5 1), bone and kidney (n 5 1), bone (n 5 2), pleura (n 5 1), intestine (n 5 1), liver (n 5 1), and soft tissue mass (n 5 1).
was defined when the ratio was #1 3 1023. Molecular relapse (MREL) was
defined as the reappearance of the BCR-ABL1 transcript after achieving MCR.
Results
Assessment of response and toxicity
Patient characteristics
BM aspirations and biopsies were performed approximately the 28th day
after induction initiation to check whether HCR was achieved. HCR
was achieved when the BM mononuclear cells comprised ,5% blasts, BM
cellularity was $25%, the absolute neutrophil count had recovered to
$1000/mm3, and the PB platelet count was $100 000/mm3. Toxicity
was graded according to the National Cancer Institute Common Toxicity
Criteria (version 2.0).
From January 2009 to May 2012, 91 subjects were enrolled in 17
centers. One subject withdrew informed consent before we assessed
hematologic response to induction therapy. Therefore, 90 subjects
were analyzable for efficacy and safety assessments. Table 2 presents
the baseline patient characteristics.
Statistics and analysis of data
Progress and outcomes of induction therapy
Nonrelapse mortality (NRM) was defined as a patient death without disease
progression, including overt hematologic relapse (HREL) and MREL.
HREL-free survival (HRFS) times were measured from the date of HCR to
the date of NRM or HREL. NRM and HREL were considered competing
risks. MREL-free survival (MRFS) times were measured from the date of
MCR to the date of NRM, MREL, or HREL. Overall survival (OS) was
measured from entry into the present study to the date of last follow-up or
death. Subjects were followed up until the end of maintenance or for 2 years
after allo-HCT. Subjects were dropped out of the current study when any of
the following events occurred: MREL that caused a change in the TKI from
nilotinib to any other drug; HREL; withdrawal of consent; major protocol
violations, such as auto-HCT administration; or death from any cause. Data
were censored for subjects that were dropped out of the current study.
Relapse-free survival (RFS) and OS were estimated with the Kaplan-Meier
method and Cox-regression method. Cumulative incidences were estimated
with the Gray method. All statistical analyses were performed with IBM
SPSS 21 (IBM Corporation) or NCSS 2004 (Number Cruncher Statistical
Systems, Kaysville, UT). All data were analyzed and finally approved by all
the authors.
The HCR rate was 91% (82 subjects), and the median time to HCR
was 27 days (range, 13-72). The remaining 8 subjects did not achieve
HCR, because of death in aplasia during induction; all 8 subjects died
of febrile neutropenia with septic shock, and in particular, 1 died of
invasive fungal pneumonia combined with intracranial hemorrhage.
At the time of HCR, the MCR achievement rate was 53% (48 of 90
subjects).
Postremission therapy
Figure 1 shows a flow diagram of treatment of all subjects. Among 82
subjects that achieved HCR, 57 (70%) received allo-HCT after the
first HCR (supplemental Table 1; see the Blood Web site). The other
25 subjects were not eligible for allo-HCT, because of dropout from
various causes (n 5 8), advanced age (n 5 8), patient refusal (n 5 4),
and no suitable donor (n 5 5). Among those without suitable donors,
2 subjects received auto-HCTs; these subjects were excluded from
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BLOOD, 6 AUGUST 2015 x VOLUME 126, NUMBER 6
NILOTINIB-BASED CHEMOTHERAPY FOR PH-POSITIVE ALL
749
Figure 1. Flow diagram shows patient treatments and dropouts. The drugs and dosing used for induction and consolidation cycles are itemized in Table 1. Con,
consolidation.
the study at the initiation of conditioning for auto-HCT because of
protocol violation.
MR and MRD
A total of 77 subjects achieved MR5 by the end of the present study.
Accordingly, the cumulative rate of MCR was 86% among all 90
subjects and 94% among the 82 subjects that achieved HCR. The
median time from treatment initiation to MCR was 1.1 months (range,
0.6-15.8). At the time of HCR, the overall MR5 rate was 56% (61%
among the 82 subjects), and the overall MR3 rate was 79% (87%
among the 82 subjects). Among the 70 evaluable subjects at 3 months
after HCR, the MR5 rate was 77%, and the MR3 rate was 87%. The
MR5 rate was 89%, and MR3 rate was 96% among subjects who
received allo-HCT, whereas the MR5 rate was 56% and MR3 rate was
72% among subjects who did not receive allo-HCT. Among 57 subjects
Figure 2. Distribution of MR to treatment. MR3 and
MR5, major and complete MRs, respectively.
that received allo-HCT, 48 (84%) achieved MR5 just before conditioning, and 47 (82%) maintained MR5 at 3 months after allo-HCT
(Figure 2).
Among 25 subjects that did not receive allo-HCT, 7 experienced
HREL, and the median time to HREL was 8.8 months (range, 3.1-23.1).
Among the other 18 subjects that were in HCR, 3 experienced MREL
with MRD levels of 6 3 1025, 10 3 1025, and 24 3 1025. When
the administration of nilotinib was continued, MRD negativity was
achieved again after 3 months, and it was maintained until the end of
follow-up in all 3 subjects.
Survival outcomes
The 2-year HRFS rate was 72% among 82 subjects that achieved HCR,
and the 2-year MRFS rate was 63% among 76 subjects that achieved
MCR. The cumulative 2-year incidence of NRM was 25% (95%
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750
KIM et al
BLOOD, 6 AUGUST 2015 x VOLUME 126, NUMBER 6
Figure 3. Survival outcomes. (A) HRFS of subjects that achieved HCR. (B) Cumulative incidence of NRM. (C) OS. (D) OS (after censoring subjects who received allo-HCT
at the time of conditioning).
confidence interval, 18% to 37%; standard error, 4.8%). The 2-year OS
rate was 72% when survival time was measured to the date of last followup or death, or 62% when we censored subjects who received allo-HCT
just before conditioning (Figure 3). The OS was similar between alloHCT recipients and nonrecipients (supplemental Figure 1).
Details of allo-HCT
Fifty-seven subjects received allo-HCTs at a median of 3.8 months
(range, 1.4-8.0) after HCR and after a median of 2 cycles (range, 0-3)
of consolidation. Most subjects (n 5 54, 95%) achieved neutrophil
engraftment, and the median time from stem cell infusion to engraftment was 15.0 days (range, 10-33). Twenty-five subjects experienced acute GVHD (44% of 57), and 12 exhibited greater than or
equal to grade 2 acute GVHD (21% of 57). The overall incidence of
chronic GVHD was 33% (19 of 57 subjects), and chronic GVHD was
extensive in 11%.
Allo-HCT outcomes (HRFS and OS) were not related to any differences in treatment, including donor differences (matched sibling
donor vs MUD vs haploidentical familial [familial mismatched]
donors), intensity of conditioning (myeloablative vs reduced intensity), total body irradiation (administered vs not administered), and
antithymocyte globulin (administered vs not administered). However,
subjects that received granulocyte colony-stimulating factor–mobilized
PB stem cells showed a superior 2-year HRFS rate compared with those
that received BM stem cells (85% vs 61%, P 5 .028).
Comparison of outcomes with and without allo-HCT
Among the 82 subjects that achieved HCR (Figure 1), the 2-year
cumulative HREL incidence was 24%. The HREL incidence was lower
in recipients of allo-HCT (n 5 57; 19%) than in nonrecipients (n 5 25;
41%). Moreover, allo-HCT recipients had significantly higher estimated
2-year HRFS rates than nonrecipients (78% vs 49%, P 5 .045).
However, the 2-year cumulative incidence of NRM (overall 19.3%) was
similar between allo-HCT recipients and nonrecipients (19% vs 20%,
respectively). Accordingly, the estimated 2-year OS was similar between
these groups (80% vs 72%, respectively; P 5 .227). Among 76 subjects
that achieved MCR, the estimated 2-year MRFS rates were not different
between nonrecipients and recipients of allo-HCT (65% vs 53%, respectively; P 5 .783).
Outcomes according to baseline characteristics
The HCR rate was not affected by most characteristics of subjects at
diagnosis, including age (,35 vs $35 or ,45 vs $45 or ,55 vs
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NILOTINIB-BASED CHEMOTHERAPY FOR PH-POSITIVE ALL
751
Figure 4. Comparison of outcomes according to MRD achievement after HCR. (A) HRFS based on whether MR3 was achieved at 3 months after HCR. (B) HRFS based
on whether MR5 was achieved at 3 months after HCR. (C) HRFS for subjects that did not receive allo-HCT, based on whether they achieved MR5 at 3 months after HCR. (D)
HRFS for allo-HCT recipients, based on whether they achieved MR3 just before allo-HCT. (E) HRFS for allo-HCT recipients, based on whether they achieved MR5 just before
allo-HCT. (F) HRFS for allo-HCT recipients, based on whether they had maintained MR5 at 3 months after allo-HCT; the group that failed to maintain MR5 included subjects
that had relapsed (MRD positive) and those that had failed to achieve MR5.
$55 years), PB WBC count (,30 000/mm3 vs $30 000/mm3), immunophenotype (biphenotypic vs ALL), leptomeningeal involvement
of leukemic cells (present vs absent), or chromosome aberration (Phalone vs an additional type). However, subjects with major BCR-ABL1
transcripts showed superior HCR rates compared with those with the
minor transcript (97% vs 76%, P 5 .005). This effect was mainly
because of different frequencies of death in aplasia during induction.
The baseline characteristics including the age differences did not affect
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BLOOD, 6 AUGUST 2015 x VOLUME 126, NUMBER 6
KIM et al
Figure 5. OS based on whether MR3 was achieved at
3 months after HCR.
the 2-year HRFS rates and 2-year OS rates, except that a high WBC
count tended to increase the risk of HREL, when analyzed as a
continuous variable (hazard ratio [HR], 1.004; P 5 .025).
HRFS according to MRD status
Subjects assessed for MRD were stratified into subgroups of MRD
levels at HCR, at 3 months after HCR, at allo-HCT, and at 3 months
after allo-HCT. The 2-year HRFS rate was not affected by whether
subjects had achieved MR3 or MR5 at HCR. However, subjects that
achieved MR3 at 3 months after HCR had significantly higher HRFS
rates than those that failed to achieve MR3. In fact, those that failed to
achieve MR3 at 3 months after HCR had 9.1-fold higher risk of HREL
(P 5 .004) than those that achieved MR3 (Figure 4A). These outcome
differences were more evident when we considered MR5 achievement
at 3 months after HCR (Figure 4B). The estimated 2-year HRFS rates
were 80% for those that achieved and 33% for those that did not achieve
MR5 (P , .001), and the HR for HREL was 6.3 (P 5 .001). Next, we
analyzed the subgroups of subjects that did or did not receive allo-HCT.
We found that, among subjects that did not receive allo-HCT,
achievement of MR5 at 3 months after HCR significantly affected the
estimated 2-year HRFS rates (64% for MR5 achievement vs 0% for
MR5 failure, P , .001). However, among subjects that received alloHCT, achievement of MR5 did not significantly affect the 2-year
HRFS rate (Figure 4C).
We found that, among 57 subjects that received allo-HCT, significant predictors of the 2-year HRFS were the failure to achieve MR3
(0% vs 83% for MR3 achievers; HR, 19.8; P 5 , .001) and MR5 (49%
vs 85% for MR5 achievers; HR, 3.8; P 5 .024) just before allo-HCT
(Figure 4D-E). The HR for HREL was 4.8 for subjects that either failed
to achieve MR5 or experienced MREL at 3 months after allo-HCT
(P 5 .016) compared those that achieved MR5 (Figure 4F).
OS according to MRD status
The OS rates were analyzed according to MRD status. The 2 subjects
that failed to achieve MR3 at 3 months after HCR did not survive;
however, the 2-year OS rate was 85% for those that achieved MR3 at 3
months after HCR (Figure 5). The HR for death was 10.6 for these
groups (P 5 .031). The failure to achieve MR3 at 3 months after HCR
was prognostic of death for the 57 subjects that received allo-HCT.
Among these subjects, the HR for death was 13.4 (P 5 .025) for those
that failed compared with those that achieved MR3 at 3 months after
HCR.
Multivariate analysis
Cox-regression analyses were performed to identify factors that
influenced the HRFS and OS. The analyses included variables that
were significant in predicting the outcome in the current study. These
variables included the performance of allo-HCT (yes vs no), the MRD
status at 3 months after HCR (MR3 vs no MR3), the PB WBC count,
and the type of BCR-ABL1 transcript (major vs minor). Both the
administration of allo-HCT (HR, 3.3; P 5 .048) and the achievement of MR3 (HR, 12.3; P 5 .038) were significant predictors of
2-year HRFS. The results were similar when the achievement of
MR5 was included instead of MR3; the administration of allo-HCT
had an HR of 3.9 (P 5 .036), and the achievement of MR5 had an
HR of 7.5 (P 5 .004). None of the variables could significantly
predict the 2-year OS.
AEs
The AEs that occurred with incidences of 5% or more during induction and consolidation cycles are shown in Table 3. Episodes of
jaundice greater than or equal to grade 3 occurred in 4% to 25%
of subjects, but most were reversed when nilotinib was reduced or
discontinued transiently. After reversal, most subjects continued to
receive nilotinib at the starting dose. The AEs related to the gastrointestinal system were generally tolerable. Although 13% of subjects
experienced greater than or equal to grade 3 serum lipase elevations,
only 2 subjects (2%) experienced greater than or equal to grade 3
overt pancreatitis during induction. Other AEs thought to be related
to nilotinib were also tolerable. Incidence of AEs related to the
cardiopulmonary system, including pleural effusion, pulmonary
edema, noncardiac chest pain, acute coronary syndrome, paroxysmal atrial tachycardia, and atrial fibrillation, was 1%.
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BLOOD, 6 AUGUST 2015 x VOLUME 126, NUMBER 6
NILOTINIB-BASED CHEMOTHERAPY FOR PH-POSITIVE ALL
753
Table 3. AEs during chemotherapy
Induction
(n 5 90)
Con #1 (n 5 80)
Con #2 (n 5 65)
Con #3 (n 5 25)
Con #4 (n 5 8)
Con #5 (n 5 7)
Total
G4
Total
G4
Total
G4
Total
G4
Total
G4
Total
G4
ANC
—
98
—
42
—
98
—
39
—
100
—
43
Platelet
—
47
—
6
—
48
—
22
—
75
—
14
Hematologic
Infection
Febrile neutropenia
—
11
—
1
—
6
—
0
—
0
—
0
Bacteremia
—
39
—
5
—
19
—
8
—
13
—
14
Other infection
13
1
4
0
5
0
12
0
13
0
0
0
Lung infection
6
1
0
0
2
0
12
0
0
0
0
0
Soft tissue infection
1
0
1
0
0
0
0
0
0
0
0
0
Others
7
0
0
0
3
0
0
0
13
0
0
0
Total
‡G3
Total
‡G3
Total
‡G3
Total
‡G3
Total
‡G3
Total
‡G3
Jaundice
87
19
81
10
73
14
61
4
63
25
57
0
ALT elevation
79
17
67
8
65
5
58
0
38
0
57
0
Azotemia
12
0
5
0
18
3
29
4
0
0
14
0
Lipase elevation
24
13
15
7
17
9
0
0
33
0
0
0
2
0
4
0
8
0
4
0
0
0
0
0
Nonhematologic
Anorexia
Nausea/vomiting
55
5
24
1
40
5
42
0
25
0
29
0
Dyspepsia
36
1
9
1
5
0
0
0
0
0
0
0
Oral mucositis
38
5
23
5
39
8
32
4
25
0
29
14
Abdominal pain
9
2
6
1
2
0
0
0
0
0
14
0
30
5
10
0
23
3
4
0
0
0
0
0
0
Diarrhea
Fecal incontinence
Constipation
Ileus
0
0
0
0
0
0
0
0
0
0
14
12
0
11
0
6
0
8
0
13
0
14
0
8
0
5
0
0
0
0
0
0
0
0
0
Pancreatitis
24
2
15
0
17
0
0
0
33
0
0
0
Hemorrhage
17
2
5
0
12
0
0
0
0
0
0
0
0
Fever
Myalgia
Headache
Seizure
2
0
4
0
8
0
4
0
0
0
0
26
2
2
3
0
0
13
0
0
0
14
0
4
1
6
0
5
0
8
0
13
0
14
0
0
0
0
0
0
2
0
4
0
0
0
0
20
1
25
0
23
2
8
0
0
0
0
0
0
0
3
0
5
0
8
0
0
0
0
0
Skin rash
16
4
6
1
32
3
16
0
13
0
14
0
Insomnia
7
0
1
1
3
0
0
0
0
0
0
0
Peripheral neuropathy
Pruritus
All values are percentiles. Dashes indicate that the number was omitted because specifying the exact number was not relevant in the table.
ANC, absolute neutrophil count; ALT, alanine aminotransferase; G4, grade 4; G3, grade 3.
All grades of QTc prolongation occurred among 66 cycles (38%) of
the total 172 evaluable induction/consolidation cycles. Only 3 episodes
(2%) were categorized as grade 3.
Administration of cytotoxic drugs and nilotinib
Table 4 shows the number of subjects that experienced AEs that caused
dose reductions or interruptions and the dose intensity of nilotinib
during chemotherapy. During induction, 45 subjects (50%) experienced 55 episodes that required dose reduction or transient interruption
of nilotinib. The causative AEs were mainly febrile neutropenia (n 5 11),
jaundice (n 5 8), nausea/vomiting (n 5 6), and lung infiltration/infection
(n 5 5). Nilotinib was not discontinued permanently because of AEs,
apart from subjects that died during induction. During induction, the
median daily dose of nilotinib was 669 mg (range, 133-800), and the
median dose intensity per day was 84% (range, 17% to 100%). Both
the number of subjects that experienced nilotinib dose reductions/
transient interruptions and the number of episodes that caused
nilotinib dose reductions/transient interruptions decreased during
subsequent consolidations. However, these events did not affect
the overall outcome, including the HRFS and OS rates, regardless of
whether subjects experienced dose reductions or interruptions in
nilotinib.
Discussion
Before the era of imatinib, the HCR rate for Ph-pos ALL was 64% to
83% with high-dose multiagent chemotherapy,12 and the median
survival time was only ;1 year.13 The introduction of imatinib into
the treatment of Ph-pos ALL has increased the HCR rate to 95% to
100%14-20 and has achieved meaningful improvement in OS.1,2,21
Despite its overall benefits, imatinib has some limitations as a treatment
of Ph-pos ALL. First, the gastrointestinal AEs of imatinib may be
aggravated when combined with cytotoxic drugs; this aggravation
results in reduced drug compliance and, consequently, reduced dose
intensity. Second, among the patients ineligible for allo-HCT that
received consolidation followed by maintenance, many relapsed
after discontinuing imatinib.22 That result suggested that even when
imatinib was included in the treatment, allo-HCT remained important
for overcoming the poor prognosis of Ph-pos ALL. The advantages of
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754
BLOOD, 6 AUGUST 2015 x VOLUME 126, NUMBER 6
KIM et al
Table 4. Details of cytotoxic drugs and nilotinib during chemotherapy
Induction (n 5 90)
Con #1 (n 5 80)
Con #2 (n 5 65)
5 (6)
15 (19)
0
Con #3 (n 5 25)
Con #4 (n 5 8)
Con #5 (n 5 7)
10 (40)
1 (1)
3 (43)
Cytotoxic drugs
Subjects with episode(s),* n (%)
Cause of episode(s),* n
AE
3
15
0
9
0
Comorbidity or age
0
0
0
1
1
1
2
Others
2
0
0
0
0
0
Median dose per day (mg)
669
800
800
800
800
800
Median dose intensity (%)
84
100
100
100
100
100
45 (50)
21 (26)
18 (28)
7 (28)
1 (13)
1(14)
55
24
26
Nilotinib
Subjects with episode(s),* n (%)
No. of episode(s),* n
8
1
1
Cause of episode(s),* n
Febrile neutropenia
11
3
2
0
0
0
Fever
1
1
1
0
0
0
Myalgia
3
0
1
0
0
0
Fatigue
1
0
0
0
0
0
Headache
1
1
0
0
0
0
Cognitive dysfunction
0
1
0
0
0
0
Lung infiltration/infection
5
2
2
0
0
0
Jaundice
8
5
3
1
1
0
Serum ALT elevation
2
2
2
0
0
0
Serum lipase elevation
2
0
1
0
0
0
Oral mucositis
0
0
0
1
0
0
Nausea/vomiting
6
2
1
0
0
0
Dyspepsia
0
1
0
0
0
0
Pancreatitis
0
0
0
0
0
1
Abdominal pain
3
0
0
0
0
0
Diarrhea
1
0
3
0
0
0
Ileus
1
2
0
0
0
0
Skin rash/itching
2
1
2
2
0
0
Edema
1
1
0
1
0
0
0
PSVT/arrhythmia
1
0
0
0
0
QTc prolongation
2
1
0
0
0
0
Palpitation
0
0
1
0
0
0
Angina
0
1
0
0
0
0
Azotemia
0
0
3
1
0
0
Peripheral neuropathy
0
0
1
0
0
0
Tremor
0
0
1
0
0
0
Cytopenia
2
0
1
2
0
0
Bleeding
1
0
0
0
0
0
Infection
0
0
1
0
0
0
Unknown
1
0
0
0
0
0
PSVT, paroxysmal supraventricular tachycardia.
*Episodes that caused dose reduction or transient interruption of drug.
nilotinib include its high in vitro affinity to BCR-ABL1 tyrosine kinase,7,8
its improved MR in the treatment of chronic-phase CML,9 and its
tolerability. Nilotinib’s low AE incidence improves drug compliance, which makes it more attractive than imatinib in the treatment of
Ph-pos ALL. Moreover, the high incidence of ABL1 kinase mutations
in Ph-pos ALL diagnoses23,24 justifies the use of nilotinib because
nilotinib can effectively inhibit various mutated BCR-ABL1 tyrosine
kinases.25
The present study showed that, other than the HCR rate, many
outcomes with nilotinib were superior to those with imatinib and
comparable to those with dasatinib.6,26 However, direct comparisons
with previous studies were difficult because of the heterogeneity of
inclusion criteria and end points (supplemental Table 2). Nilotinib
was associated with AE types and severity similar to those of
imatinib or dasatinib, when combined with cytotoxic drugs. During
induction, we found 13% to 19% incidences of grades 3 or 4 jaundice,
ALT elevations, and lipase elevations. However, most of these AEs
were reversible after dose reduction or transient interruption of
nilotinib. Most subjects continued with nilotinib for the intended
period at a full or reduced dose. Grade 3 or 4 QTc prolongation
occurred in only 2% of subjects. The AEs related to allo-HCT,
particularly the incidence and severity of acute and chronic GVHD,
were not significantly different from those typically found in clinical
practice.
We found that MRD levels at 3 months after HCR were correlated
with the overall outcomes, consistent with previous reports.27-30
Interestingly, the achievement of MR5 significantly affected the
2-year HRFS rate of subjects that did not receive allo-HCT, but not
that of subjects that received allo-HCT. It was encouraging to find
that, among subjects that achieved MR5, the 2-year HRFS rate was
similar between those that did not receive allo-HCT (64%) and those
that received allo-HCT (78%). A recent study by Wetzler et al31 also
showed that the OS and HRFS were similar between those who
underwent auto-HCT and those who underwent allo-HCT. These
results suggested that administering TKI plus chemotherapy followed by TKI maintenance with or without auto-HCT may provide
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BLOOD, 6 AUGUST 2015 x VOLUME 126, NUMBER 6
similar outcomes to those achieved by administering allo-HCT, if the
patient achieves deep MR during the early postremission period.
It should be emphasized that in the current study, a significant
portion of patients that failed to achieve a good MR (MR3 or MR5) at
3 months after HCR could be rescued successfully with allo-HCT.
The estimated 2-year HRFS rate was 33% for those that did not
achieve MR5. Also, 1 of 2 patients that failed to achieve even MR3
remained in HCR for 2 years after allo-HCT. The multivariate
analysis showed that both the administration of allo-HCT and the
achievement of deep MR at early postremission times were important. These results suggested that allo-HCT continued to play a
significant role in treating Ph-pos ALL, despite the advent of potent
TKIs, such as nilotinib. Therefore, in future MRD-based strategies
for Ph-pos ALL, active administration of allo-HCT should be considered for patients that show suboptimal early MRD responses to
a TKI plus multiagent chemotherapy.
Patients that failed to achieve a good MR (MR3 or MR5) just before
allo-HCT had a significantly higher risk of HREL than those that
achieved good MRs. Patients that failed to achieve MR5 or showed
early MREL at 3 months after allo-HCT were at high risk of HREL.
Future studies should consider early interventions, including post–alloHCT empirical TKI administration, donor lymphocyte infusion, and/or
a second-line TKI, to reduce the risk of post–allo-HCT HREL.
The limitation of the current study was that this study was not
performed in a randomized comparative way, and the advantages of
nilotinib over other TKIs were not definitely demonstrated. Although
the combination of nilotinib and chemotherapy was feasible, the AEs
cannot be overlooked. Moreover, the HCR rate was relatively lower
than those reported for imatinib or dasatinib, which reported the high
remission rates with low induction mortality using more minimal
cytotoxic chemotherapeutic agents.6,26 The relatively low HCR rate
was mainly because of the high NRM rate we observed during
induction in the current study, and future studies should investigate
whether a combination of nilotinib and less intensive cytotoxic chemotherapeutic agents might achieve improved outcomes and decrease
NRM rates in a randomized comparative way.
To the best of our knowledge, the present study was the first phase 2
prospective trial of nilotinib plus multiagent chemotherapy for adult
patients with Ph-pos ALL. Although the NRM rate was relatively high,
because of high doses of anthracycline and nilotinib during induction,
we found a high cumulative incidence of MCR (negative MRD) and
HRFS rates comparable to those reported previously with imatinib or
dasatinib. Furthermore, nilotinib was well-tolerated during consolidation with cytotoxic drugs. The MRD status at 3 months after HCR was
closely related to the HRFS. Moreover, the MRD levels just before and
at 3 months after allo-HCT were predictive of the HREL after alloHCT. We recommend that future studies evaluate whether, compared
with imatinib or dasatinib, nilotinib may improve the outcome of
Ph-pos ALL by decreasing the HREL rate and decreasing the proportion
of patients that require allo-HCT.
Acknowledgments
The authors thank the staffs of the participating institutes in the Adult
Acute Lymphoblastic Leukemia Working Party of the Korean
Society of Hematology, especially Hun Mo Ryoo, Sung Hwa Bae,
NILOTINIB-BASED CHEMOTHERAPY FOR PH-POSITIVE ALL
755
Min Kyoung Kim, Moo-Rim Park, Hyeok Shim, Joon Seoung Park,
Seong Hyun Jeong, Byung Soo Kim, Yong Park, and Hong Ghi Lee
for participating in the study group and advising the study as members
of the steering committee.
This work was supported by research funding from Novartis,
which provided nilotinib and laboratory costs for monitoring MRD
(CAMN107A2403), and by a grant from the Asan Institute for Life
Sciences, Asan Medical Center, Seoul, Korea (2010-0668).
Authorship
Contribution: K.-H.L. contributed to the study design; D.-Y.K.
and K.-H.L. contributed to the literature search, data interpretation, and writing the manuscript; D.-Y.K., Y.-D.J., and S.-N.L.
conducted the study; Y.-U.C., S.J., C.-J.P., and H.-S.C. collected
the blood samples for MRD evaluation, performed the laboratory
process, and analyzed the results; and all the authors contributed
to the data collection, data analysis, and final approval of the
manuscript.
Conflict-of-interest disclosure: D.-Y.K. has received personal fees
from Bristol Myers Squibb, Novartis, Otsuka, and Merck. K.-H.L. has
received research grant support from Novartis Korea. The remaining
authors declare no competing financial interests.
A complete list of the members of the Adult Acute Lymphoblastic
Leukemia Working Party of the Korean Society of Hematology appears in “Appendix: study group members.”
Correspondence: Kyoo-Hyung Lee, Department of Hematology,
Asan Medical Center, University of Ulsan College of Medicine, 88,
Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea; e-mail: khlee2@
amc.seoul.kr.
Appendix: study group members
The members of the Adult Acute Lymphoblastic Leukemia Working
Party of the Korean Society of Hematology are: Kyoo-Hyung Lee,
Young-Don Joo, Byoung Kook Kim, Jae Hoo Park, Hyun-Sook Chi,
Whi-Hoong Yoon, Seonyang Park, Kyung Sam Cho, Yoo Hong
Min, Hong Ghi Lee, Chan-Jeoung Park, Chul-Soo Kim, Jong-Ho
Won, Hyeoung Joon Kim, Byung Soo Kim, Sung-Soo Yoon, Chul
Won Jung, Je-Hwan Lee, Jae Hoon Lee, Sang Kyun Sohn, Yang Soo
Kim, Je-Jung Lee, Deog-Yeon Jo, Joo-Seop Chung, Seok Lee,
Jae-Young Kwak, Joon Seoung Park, Kihyun Kim, Inho Kim,
Myung Soo Hyun, Jung Lim Lee, Hun Mo Ryoo, Moo-Rim Park,
Hyeon-Seok Eom, Jun Ho Jang, Chul Won Choi, Jinny Park,
Ho Young Kim, Hyo Jung Kim, Dae Young Zang, Ho-Jin Shin,
Hyeok Shim, Seongsoo Jang, Dong Hwan (Dennis) Kim, Jung-Hee
Lee, June-Won Cheong, Jin Seok Kim, Sung-Hyun Kim, Seok Jin
Kim, Hawk Kim, Sung Hwa Bae, Won Sik Lee, Yeung-Chul Mun,
Chan-Kyu Kim, Deok-Hwan Yang, Seong Hyun Jeong, Sang Min
Lee, Gyeong Won Lee, Young-Uk Cho, Min Kyoung Kim,
Dae-Young Kim, Joon Ho Moon, Ho-Sup Lee, Sung-Nam Lim,
Sung-Doo Kim, Se Hyung Kim, Jae-Sook Ahn, Yong Park, Hyewon
Lee, Kyoung Ha Kim, and Jae-Cheol Jo.
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
756
KIM et al
BLOOD, 6 AUGUST 2015 x VOLUME 126, NUMBER 6
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From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
2015 126: 746-756
doi:10.1182/blood-2015-03-636548 originally published
online June 11, 2015
Nilotinib combined with multiagent chemotherapy for newly diagnosed
Philadelphia-positive acute lymphoblastic leukemia
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Dong Hwan (Dennis) Kim, Kihyun Kim, Chul Won Jung, Inho Kim, Sung-Soo Yoon, Seonyang Park,
Jae-Sook Ahn, Deok-Hwan Yang, Je-Jung Lee, Ho-Sup Lee, Yang Soo Kim, Yeung-Chul Mun, Hawk
Kim, Jae Hoo Park, Joon Ho Moon, Sang Kyun Sohn, Sang Min Lee, Won Sik Lee, Kyoung Ha Kim,
Jong-Ho Won, Myung Soo Hyun, Jinny Park, Jae Hoon Lee, Ho-Jin Shin, Joo-Seop Chung, Hyewon
Lee, Hyeon-Seok Eom, Gyeong Won Lee, Young-Uk Cho, Seongsoo Jang, Chan-Jeoung Park,
Hyun-Sook Chi and Kyoo-Hyung Lee
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