181 High and Early Rates of Cytogenetic and Molecular Response with Nilotinib 800 Mg Daily as First
Line Treatment of Ph-Positive Chronic Myeloid Leukemia in Chronic Phase: Results of a Phase 2 Trial
of the GIMEMA CML Working Party
Monday, December 8, 2008: 7:00 AM
Halls B and C (Moscone Center)
Gianantonio Rosti1*, Fausto Castagnetti1*, Angela Poerio1*, Massimo Breccia2*, Luciano Levato3*, Adele
Capucci4*, Mario Tiribelli5*, Fabio Stagno6*, Alfonso Zaccaria7*, Tamara Intermesoli8*, Bruno Martino9*,
Monica Bocchia10*, Michele Cedrone11*, Francesco Bartucci12*, Francesca Palandri1*, Gabriele Gugliotta1*,
Nicoletta Testoni1*, Giuliana Alimena13, Giovanni Martinelli1*, Fabrizio Pane, MD14, Giuseppe Saglio15* and
Michele Baccarani1*
1Institute of Hematology Seragnoli, Bologna, Bologna, Italy
2University of Rome – La Sapienza, Italy
3Hematology Unit, Catanzaro, Italy
4Hematology Unit, Brescia, Italy
5Chair of Hematology, Udine, Italy
6Chair of Hematology, Catania, Italy
7Ematologia-Ravenna, Italy
8Chair of Hematology, Bergamo, Italy
9Reggio Calabria Hospital
10Chair of Hematology, University of Siena, Italy
11Hematology Unit, "San Giovanni-Addolorata" Hospital, Roma, Italy
12Novartis Pharma, Origgio (VA), Italy
13Division of Hematology-Dept. of Cellular Biotechnologies and Hematology, University La Sapienza of Rome,
Rome, Italy
14A.F. di Oncologia Ematologica Diagnostica, Azienda Ospedaliera, Napoli, Italy
15Internal Medicine and Hematology, Università di Torino - Ospedale San Luigi, Orbassano, Italy
Imatinib (IM) 400 mg daily is the standard treatment for chronic myeloid leukemia in early chronic phase (ECP):
the results of the IRIS trial have shown a 72 months overall survival of 95%; EFS and PFS were 83% and 93%,
respectively; the cumulative rate of complete cytogenetic response (CCgR) for the IM 400 mg arm was 25% at 3
months (at 6, 12, 18 and 60 months it was 51%, 69%, 76% and 87%, respectively). Nilotinib, a second
generation TKI, has a higher binding affinity and selectivity for Abl with respect to IM, being 20 to 50 times more
active in IM-sensitive cell lines and is highly effective in IM resistant patients, across every disease phase. To
investigate the therapeutic efficacy and the safety of nilotinib 400 mg BID in untreated, ECP, Ph-pos CML
patients, the italian GIMEMA CML Working Party is conducting an open-label, single stage, multicentric, phase II
study trial (ClinicalTrials.gov. NCT00481052); all patients provided written informed consent. The primary
endpoint is the CCgR rate at 1 year; the kinetic of molecular response is studied by Q-PCR baseline and after
1, 2, 3, 6, 9 and 12 months from treatment start. PATIENTS Seventy-three patients have been enrolled from 20
Centres between June, 2007 and February, 2008. The median age was 51 years (range 18-83), 45% low, 41%
intermediate and 14% high Sokal risk. Median follow-up is currently 210 days (range 68-362). RESULTS All 73
patients and 48/73 (66%) completed 3 and 6 months on treatment, respectively. Response at 3 and 6 months
(ITT): the CHR rate was 100% and 98%, the CCgR rate 78% and 96%, respectively. A MMR, defined as a BCR-
ABL:ABL ratio < 0.1% according to the International Scale, was achieved by 3% of all treated patients after 1
month on treatment, but this proportion rapidly increased to 22% after 2 months, 59% after 3 months and 74%
after 6 months. One patient progressed at 6 months to accelerated-blastic phase with the T315I mutation.
NILOTINIB DOSE AND COMPLIANCE No dose escalation was permitted in case of resistance; the median daily
average dose was close to the intended dose, 789 mg (range 261 – 800); 34/73 patients (47%) interrupted
nilotinib at least once, with a median duration of dose interruption of 15 days (range 2-98). The dose of nilotinib
at the last visit was 400 mg BID for 52 patients (71%), 400 mg daily for 20 patients (27%) and 200 mg daily for 1
patient (1%). ADVERSE EVENTS: AEs (grade III/IV) were manageable with appropriate dose adaptations:
hematologic toxicity was recorded so far in 4 pts (5% - only 1 event grade IV neutropenia); the most frequent
biochemical laboratory abnormalities (grade III) were total bilirubin increase (15%), GOT/GPT increase (11%)
and lipase increase (4%). Only 1 episode of grade IV lipase increase was recorded. It is noteworthy,
considering the 48 cases with at least 6 months of follow-up, that the incidence of any grade II and III non-
hematologic adverse event, decreased from 50% and 8% (first 3 months) to 23% and 6% (second trimester),
respectively. ECG monitoring: in 16 patients (22%), transient and not clinically relevant ECG abnormalities have
been recorded; 2 more patients (3%) revealed a transient and uneventful QTc prolongation (>450 but <499
msec). CONCLUSIONS: The results that have been achieved in these unselected patients and within a
multicentric trial, strongly support the notion that in ECP Ph-pos CML patients both cytogenetic and molecular
responses to nilotinib are substantially faster than the responses to IM.
446 Efficacy of Nilotinib (formerly AMN107) in Patients (Pts) with Newly Diagnosed, Previously
Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic
Phase (CML-CP)
Monday, December 8, 2008: 1:45 PM
2009-2011-2022-2024 - West (Moscone Center)
Jorge Cortes1, Susan O'Brien2, Dan Jones2*, Alessandra Ferrajoli2*, Marina Konopleva2*, Gautam
Borthakur2*, Guillermo Garcia-Manero2*, Laurie A. Letvak3 and Hagop Kantarjian2*
1M.D. Anderson Cancer Center, Houston, TX
2The University of Texas M.D. Anderson Cancer Center, Houston, TX
3Novartis Oncology, East Hanover, NJ
Background: Nilotinib is an oral tyrosine kinase inhibitor with high selectivity towards Bcr-Abl and approximately
30-fold more potent than imatinib, and is effective in patients with CML after imatinib failure. We initiated a
phase II study to evaluate the efficacy of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP. Aims:
To investigate the efficacy and safety of nilotinib as initial therapy for patients with CML-CP. Methods: The
primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months
(mo). Pts with untreated CML-CP (or with <1 months of therapy with imatinib) were eligible and received nilotinib
400mg twice daily. A cohort of patients with previously untreated CML in accelerated phase (AP) was also
included. Results: Forty-nine pts have been treated for a median of 13 months (mo). The median age was 47
years (yrs) (range, 21 to 81); 69% are Sokal low risk. Eight (16%) had received imatinib for <1 months. Overall,
46/48 (96%) of evaluable CP pts achieved a complete cytogenetic response [CCyR]. The rate of CCyR at 3, 6
and 12 mo for pts in CP compares favorably to those observed in historical controls treated with imatinib 400mg
or 800 mg daily:
Months on therapy
Percent with CCyR (No. evaluable)
P value
Nilotinib
Imatinib 400mg
Imatinib 800mg
3
93 (45)
37 (49)
62 (202)
< 0.0001
6
100 (36)
54 (48)
82 (199)
< 0.0001
12
96 (27)
65 (48)
86 (197)
0.0003
18
92 (12)
68 (38)
89 (179)
0.0042
24
91 (11)
70 (40)
88 (173)
0.0151
MMR was observed in 45% at 6 mo and 52% at 12 mo. Two of 44 (5%) evaluable pts have achieved confirmed
complete molecular response, and 3 others unconfirmed (ie, only achieved on their last assessment). Grade 3-
4 hematologic toxicity (transient) included thrombocytopenia in 10%, neutropenia in 12%, and anemia in 2%.
Grade 3-4 non-hematologic adverse events (regardless of causality) included elevation of bilirubin in 8% and
lipase in 6%. 19 (36%) pts had transient treatment interruptions and 17 (32%) had dose reductions. The actual
median dose is 800mg daily. Three pts have come off study: 1 pt's choice and 2 because of toxicity (1 liver, 1
pericardial effusion). One of them (liver toxicity) transformed to blast phase shortly after coming off study.
Estimated 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 95%.
Conclusion: Nilotinib 400 mg twice daily induces a CCyR in nearly all patients as early as 3 months after the
start of therapy with a favorable toxicity profile. Accrual is ongoing.
3216 Nilotinib Efficacy According to Baseline BCR-ABL Mutations in Patients with Imatinib-Resistant
Chronic Myeloid Leukemia in Chronic Phase (CML-CP)
Monday, December 8, 2008
Hall A (Moscone Center)
Andreas Hochhaus, MD1, Dong-Wook Kim, MD, PhD2, Giovanni Martinelli, MD3, Timothy P. Hughes, MD4,
Simona Soverini, PhD3*, Susan Branford, PhD5*, Martin C Müller, MD6*, Philipp Erben, MD7*, Ariful Haque8*,
Yaping Shou, MD, PhD9*, Giuseppe Saglio, MD10 and Jerald P. Radich, MD11
1Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany
2Hematology, St. Mary's Hospital, Seoul, South Korea
3Department of Hematology/Oncology “L. and A. Seràgnoli”, University of Bologna, Bologna, Italy
4Haematology Division, Hanson Institute Center for Cancer, Adelaide, Australia
5Division of Haematology, Hanson Institute Center for Cancer, Adelaide, Australia
6Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
7Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany
8Novartis Pharmaceuticals, Florham Park, NJ
9Novartis Institutes for BioMedical Research, Cambridge, MA
10Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
11Fred Hutchinson Cancer Research Center, Seattle, WA
Resistance or intolerance to imatinib in CML-CP occurs in ~20-30% of cases. The most frequent cause of
resistance is clonal selection of cells harboring BCR-ABL kinase domain mutations. Nilotinib is a rationally
designed, selective and potent BCR-ABL inhibitor with activity against most BCR-ABL mutants (not T315I)
indicated for the treatment of Ph+ CML patients (pts) in chronic (CP) or accelerated phase (AP) resistant or
intolerant to prior therapy including imatinib. This subanalysis of a phase II study of nilotinib in imatinib-resistant
CML-CP pts assessed the occurrence of BCR-ABL mutations at baseline and during nilotinib treatment and
their impact on treatment outcome after 12 months of nilotinib therapy. Of 321 CML-CP pts, 281 (88%) had
baseline mutation data available, 114/281 (41%) had detectable BCR-ABL mutations prior to nilotinib therapy.
The frequency of mutations at baseline was 55% among imatinib-resistant pts (n=192) and 10% among imatinib-
intolerant pts (n=89). 23% of imatinib-resistant pts had mutations that were sensitive to nilotinib in vitro (IC50
≤150 nM). These 12 different mutations (n=44) spread across the entire BCR-ABL kinase domain including P-
loop, A-loop, and other regions. 14% of imatinib-resistant pts had 3 mutations that were less sensitive to
nilotinib in vitro (IC50 >150 nM; Y253H, E255K/V, and F359C/V) and another 15% had a total of 16 mutations
with unknown sensitivity to nilotinib. In imatinib-resistant pts lacking baseline mutations, after 12 months of
therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in
40%, and major molecular response (MMR) in 28% of pts. In pts with detectable mutations, 51% achieved
MCyR, 32% CCyR, and 20% MMR. Cytogenetic response rates in pts harboring mutations sensitive to nilotinib
(MCyR 59%; CCyR 41%) or mutations with unknown sensitivity to nilotinib (MCyR 63%; CCyR 50%;) were
comparable to those for pts without baseline mutations (MCyR 60%; CCyR 40%). Pts with mutations less
sensitive to nilotinib in vitro had less favorable response after 12 months of therapy (23% MCyR). Pts with
baseline mutations had a higher rate of disease progression during nilotinib treatment compared to pts without
baseline mutations (46% vs. 26%). Different rates of progression were also observed with different mutations:
34% (15/44) of pts with mutations sensitive to nilotinib vs. 69% (18/26) with mutations less sensitive to nilotinib
progressed. Mutations most frequently associated with progression were E255K/V (6/7) and F359C/V (9/11).
Progression was defined as any of the following: investigator’s evaluation as progression, development of CML-
AP or blast crisis, loss of CHR, loss of MCyR. During nilotinib therapy, 48/281 (17%) pts had newly detectable
mutations, which were more frequent in pts with baseline mutations than in pts without baseline mutations (29%
vs. 9%, respectively). The majority of pts without baseline mutations also did not have newly detectable
mutation at the time of progression (n=14/18) suggesting that pts without baseline mutations are less likely to
progress due to newly detectable mutations. In the 63 pts who progressed, 29% had no detectable mutation at
progression, suggesting the involvement of alternative mechanisms of resistance in these pts. Overall, nilotinib
treatment results in significant cytogenetic responses in pts with imatinib-resistant CML-CP with or without BCR-
ABL mutations. The majority of imatinib-resistant pts with detectable BCR-ABL mutations at baseline also
responded to nilotinib. Pts with BCR-ABL mutations sensitive and with unknown sensitivity to nilotinib in vitro
achieved significant response rates with nilotinib therapy, comparable to those for pts without baseline
mutations.
3238 Nilotinib in Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) with Imatinib
Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study
Monday, December 8, 2008
Hall A (Moscone Center)
Hagop M Kantarjian1, Francis Giles, MD2, Kapil N. Bhalla, MD3*, Richard A. Larson, MD4, Norbert Gattermann,
MD5, Oliver G. Ottmann, MD6*, Ariful Haque, M.S.7*, Neil J. Gallagher, MD, PhD8, Michele Baccarani, MD9* and
Philipp D. le Coutre, MD10
1The University of Texas M. D. Anderson Cancer Center, Houston, TX
2The Institute for Drug Development, CTRC, University of Texas Health Science Center, San Antonio, TX
3H. Lee Moffit Cancer Center, University of South Florida, Tampa, FL
4University of Chicago, Chicago, IL
5Heinrich-Heine-University, Düsseldorf, Germany
6Department of Medicine, Hematology/Oncology, University Hospital of Frankfurt, Frankfurt, Germany
7Novartis Pharmaceuticals, Florham Park, NJ
8Oncology, Novartis Pharma AG, Basel, Switzerland
9Institute of Hematology and Medical OncologySeragnoli, Bologna, Italy
10Department of Hematology and Oncology, Charité - Humboldt-Universitat, Campus Virchow, Berlin, Germany
Background: Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor approved for the treatment of
Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic (CML-CP) or accelerated phase
(CML-AP) who are resistant or intolerant to prior therapy including imatinib. Methods: This open-label, single-
arm, phase 2 study was designed to evaluate the efficacy and safety of nilotinib in CML-CP patients resistant or
intolerant to imatinib. Imatinib intolerant patients with prior major cytogenetic response (MCyR) on imatinib were
not eligible for this trial. Nilotinib was dosed at 400 mg twice daily with the option of dose escalation to 600 mg
twice daily if responses were inadequate. Rate of MCyR was the primary endpoint. Secondary endpoints
included complete cytogenetic response (CCyR), complete hematological response (CHR), duration of MCyR,
survival, and safety. Results: A total of 321 CML-CP patients (71% imatinib-resistant; 29% imatinib-intolerant)
were evaluated. Most patients were heavily pretreated with 72% having received more than 600 mg/day of
imatinib prior to study entry. Furthermore, imatinib-intolerant patients could not have achieved prior MCyR on
imatinib therapy. Median duration of prior imatinib treatment was 33 months (range 0.3–95 months). Dose
reductions (25%) and discontinuations (15%) due to adverse events were infrequent on nilotinib therapy and
median dose intensity (788 mg/day; range 151-1112 mg/day) closely approximated the planned dose. Median
duration of exposure was 465 days (15.5 months). Overall, nilotinib therapy resulted in rapid and durable
hematologic and cytogenetic responses. Of all imatinib-resistant and –intolerant patients, 58% achieved MCyR
(1 month median time to MCyR), with 72% of patients having a baseline CHR achieving MCyR. The MCyR rate
was 63% in imatinib-intolerant and 56% in imatinib-resistant patients, respectively. Overall, 42% of patients
achieved a CCyR (50% in imatinib-intolerant and 39% in imatinib-resistant patients, respectively). Responses
were durable, with 84% of patients maintaining their MCyR at 18 months. Estimated overall survival (OS) rates
at 12 and 18 months were 95% and 91%, respectively. Nearly half of all patients (47%) were still receiving
nilotinib at the time of cut-off for data analysis. Longer follow-up has not significantly changed the safety profile
of nilotinib. The most frequently reported grade 3/4 biochemical laboratory abnormalities were elevated lipase
(16%), hypophosphatemia (15%), hyperglycemia (12%), and elevated total bilirubin (7%). Overall, biochemical
laboratory abnormalities were transient and clinically asymptomatic. Grade 3/4 non-hematologic adverse events
were infrequent with rash, headache, and diarrhea occurring in only 2% of patients. No pleural or pericardial
effusions were documented during nilotinib therapy. The most common grade 3/4 hematological laboratory
abnormalities included neutropenia (30%), thrombocytopenia (28%), and anemia (10%). Overall, QTcF
changes greater than 60 milliseconds from baseline were infrequent, occurring in only 8 patients (2.5%), and
QTcF prolongation >500 milliseconds was uncommon (<1%), occurring in only 3 patients. Brief dose
interruptions were sufficient to manage most adverse events. Conclusions: Nilotinib is highly effective and
produces rapid and durable responses in CML-CP patients who failed prior therapy including imatinib due to
resistance or intolerance and is an important treatment option for this patient population. Nilotinib is well
tolerated with minimal occurrence of grade 3/4 adverse events; safety profile has not changed with longer follow-
up.
3234 Efficacy and Tolerability of Nilotinib in Chronic Myeloid Leukemia Patients in Chronic Phase
(CML-CP) Who Failed Prior Imatinib and Dasatinib Therapy: Updated Results of a Phase 2 Study
Monday, December 8, 2008
Hall A (Moscone Center)
Francis Giles, MD1, Philipp D. le Coutre, MD2, Kapil N. Bhalla, MD3*, Gert J Ossenkoppele, MD, PhD4, Giuliana
Alimena, MD5*, Ariful Haque, M.S.6*, Neil J. Gallagher, MD, PhD7 and Hagop M Kantarjian8
1The Institute for Drug Development, CTRC, University of Texas Health Science Center, San Antonio, TX
2Department of Hematology and Oncology, Charité - Humboldt-Universitat, Campus Virchow, Berlin, Germany
3H. Lee Moffit Cancer Center, University of South Florida, Tampa, FL
4Department of Hematology, VU University Medical Center, Amsterdam, Netherlands
5Division of Hematology-Dept. of Cellular Biotechnologies and Hematology, University La Sapienza, Rome, Italy
6Novartis Pharmaceuticals, Florham Park, NJ
7Oncology, Novartis Pharma AG, Basel, Switzerland
8The University of Texas M. D. Anderson Cancer Center, Houston, TX
Background: Treatment options are limited for patients with Philadelphia chromosome-positive (Ph+) CML who
are resistant or intolerant to both imatinib and dasatinib. Nilotinib is a potent and highly selective BCR-ABL
kinase inhibitor approved for the treatment of Ph+ CML patients in chronic (CML-CP) or accelerated phase
(CML-AP) who are resistant or intolerant to prior therapy including imatinib. Here we report the updated results
evaluating the safety and efficacy of nilotinib in patients with CML-CP who were either resistant or intolerant to
both imatinib and dasatinib therapy. Methods: Nilotinib was dosed at 400 mg twice daily with an option to dose
escalate to 600 mg twice daily in patients with inadequate hematologic and/or cytogenetic responses or disease
progression. Results: A total of 37 patients (median age 62 years) with CML-CP were included in the analysis.
The median time since first diagnosis of CML was 86 months. The median duration of prior imatinib therapy was
40.6 months with 84% being imatinib-resistant and 16% imatinib-intolerant. The median duration of prior
dasatinib therapy was 6.6 months, with the majority of patients (65%) being intolerant to dasatinib therapy and
32% of patients were dasatinib resistant. Approximately half (51%) of the patients discontinued dasatinib due to
grade 3/4 laboratory abnormalities or adverse events (AEs) and 32% discontinued due to disease progression.
The median duration of nilotinib exposure was 218 days (7.3 months; range 43–723 days) and 65% of patients
remained on nilotinib at the time of data cut-off. In total, only 4 (11%) patients discontinued nilotinib due to AEs
and 9 (24%) discontinued due to disease progression. For CML-CP patients without complete hematologic
response (CHR) at baseline, 81% achieved CHR with nilotinib treatment. The median time to first CHR for
patients with confirmed HR was 1 month. Major cytogenetic response (MCyR) was achieved in 38% of patients
with median time to first MCyR being 1 month and median duration of MCyR being 9.7 months. Complete
cytogenetic response (CCyR) was achieved in 18% of patients. Estimated 1-year overall survival was 97%. The
most frequent drug-related non-hematologic AEs on nilotinib were rash (22%), nausea (16%), and pruritus
(14%). Newly occurring or worsening grade 3/4 hematologic laboratory abnormalities included neutropenia
(38%), thrombocytopenia (24%), and anemia (5%). Other common grade 3/4 biochemical laboratory
abnormalities included elevated lipase (24%), hyperglycemia (11%), elevated alanine aminotransferase (8%),
and hypophosphatemia (8%). Brief dose interruptions were sufficient to manage most adverse events.
Conclusions: Nilotinib is highly active in heavily pretreated CML-CP patients who failed both prior imatinib and
dasatinib therapy. Importantly, most patients in this study were previously intolerant to dasatinib, and
discontinuation of nilotinib in this study was uncommon. These results support nilotinib’s significant efficacy and
favorable tolerability profile demonstrated in earlier trials with nilotinib as second-line therapy for the treatment
of CML-CP. The frequency of adverse events among these heavily pretreated patients is low and similar to
patients who failed imatinib only.
3244 Molecular Responses to Dasatinib and Nilotinib in Patients with Chronic Myeloid Leukemia in
Chronic Phase (CML-CP)
Monday, December 8, 2008
Hall A (Moscone Center)
Alfonso Quintás-Cardama1*, Hagop Kantarjian2*, Franziska Michor3*, Adam Olshen4*, Mithat Gonen4*, Dan
Jones5, Mary Beth Rios2, Susan O'Brien6* and Jorge Cortes, MD1
1Leukemia, M.D. Anderson Cancer Center, Houston, TX
2M.D. Anderson Cancer Center, Houston, TX
3Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY
4Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New City, NY
5Hematopathology, UT M.D. Anderson Cancer Ctenter., Houston, TX
6Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Background: Nilotinib (NIL) and dasatinib (DAS) have a 1- and 2-log higher inhibitory potency than imatinib
against ABL1 kinase respectively, and are active against all BCR-ABL1 kinase mutants, except T315I. We
investigated the molecular responses to nilotinib and dasatinib in patients (pts) with CML-CP receiving these
agents either in the frontline (FL) or the post-imatinib failure (PIF) settings.
Methods: 205 pts with CML-CP received either NIL (n=87; 48 FL, 39 PIF) or DAS (n=118; 48 FL, 70 PIF) at
various doses in phase II studies. Quantitative reverse transcription PCR in peripheral blood samples was
performed prior to NIL or DAS start, after 1 mo of therapy, and every 3 mo thereafter.
Results: Table 1 illustrates the BCR-ABL1/ABL1 ratios at different time-points during therapy. No significant
differences were observed regarding the median baseline BCR-ABL1/ABL1 ratio across groups (p=0.88) or the
median at 12 mos between the NIL and the DAS cohorts (p=0.14). We developed an exponential model with one
population-based shape parameter and a subject-specific slope and intercept. We estimate the shape
parameter, after merging all data from a treatment group, using non-linear least squares. With the shape
parameter fixed, we estimate the subject-specific parameters using traditional least squares. A statistically
significant difference between the shape parameters of the NIL-FL and the DAS-FL treatments was observed
(p=0.005), with NIL inducing a sharper early decline in BCR-ABL1 transcripts. Our exponential model does not
fit as well for NIL-PIF vs DAS-PIF, particularly for the latter, possibly due to differences in the number and types
of mutations at the start of therapy. Indeed, DAS-resistant mutations (L248V/R, Q252H, E255K, V299L,
T315I/A, and F317L/C/I/S/V) were detected in 7 (32%) of 22 patients carrying mutations (all PIF), while NIL-
resistant mutations (Q252H, Y253H/F, E255K/V, T315I/A, F359V, V379I) were only found in 1/16 (6%) carrying
mutations (all PIF).
BCR-ABL1/ABL1 ratio reductions occurred in 73 (87%)of 84 pts who had at least 2 PCR analyses during NIL
therapy: <1-log in 7 (8%) pts, >1-log in 16 (19%) pts, >2-logs in 18 (21%) pts, and >3-logs in 32 (38%) pts.
BCR-ABL1/ABL1 ratio reductions occurred in 102 (92%) of 111 pts who had at least 2 PCR analyses during
DAS therapy: <1-log in 20 (18%) pts, >1-log in 17 (15%) pts, >2-logs in 24 (22%) pts, and >3-logs in 41 (37%)
pts. Major molecular response (MMR) and complete molecular response (CMR; undetectable BCR-ABL1
transcripts) rates were 39%/12% and 38%/7% for the NIL and DAS cohorts, respectively (50%/17% and 58%
/7% for pts receiving NIL and DAS as frontline therapy). The MMR and CMR response rates for NIL and DAS
among pts with mutations at the start of therapy were 19%/6% and 20%/0%, respectively.
Conclusion: NIL and DAS induce molecular responses in a significant number of pts, particularly when used in
the frontline setting. Although molecular responses occur across a broad variety of BCR-ABL1 kinase
mutations, CMR in this setting is a rare occurrence. NIL appears to induce faster molecular responses than
DAS, al least in the FL setting. Longer follow-up is necessary to establish the clinical consequences of this
phenomenon.
Table 1. BCR-ABL1 transcript dynamics by treatment and cohort
DRUG/COHORT
DAS
DAS-FL
DAS-PIF
NIL
NIL-FL
NIL-PIF
No. Patients
118
48
70
87
48
39
Baseline median BCR-ABL1/ABL1 (%)
70.65 (0.009-100)
36.27 (0.01-100)
75.04 (0.009-100)
67.71 (0.01-100)
71.26 (0.01-100)
53.15 (0.15-100)
Time nadir PCR (mos)
27
24
27
27
21
27
Median BCR-ABL1/ABL1 (%) nadir
0.05 (0-100)
0.01 (0.001-0.65)
0.08 (0-100)
0.07 (0-30.52)
0.01 (0-0.6)
0.16 (0-30-54)
No. Evaluable at
nadir PCR
13
21
18
17
3
10
Median BCR-ABL1/ABL1 (%) at 12 months
0.33 (0-100)
0.155 (0-100)
1.49 (0-100)
0.09 (0-92.29)
0.025 (0.01-16.21)
0.75 (0-92.29)