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Dropled Digital PCR May Have a Prognostic Value for Predicting Relapse after Imatinib Discontinuation
Abstracts Table Estimated PFS and OS at 3-Years Past Landmark by BCR-ABL1 Level Landmark/Response
n
PFS
*p -value
n
OS
3 mo BCR-ABL1 0.1%
32
97%
—
33
97%
BCR-ABL1 >0.1-1% BCR-ABL1 >1%-10%
47 51
70% 61%
.39 .0080
48 55
85% 81%
.60 .13
BCR-ABL1 >10%
82
54% overall:
.0003 0.0013
94
78% overall:
.16 0.34
58 42
91% 60%
— .0023
61 44
93% 83%
— .036
30 57
61% 53%
32 74
90% 78%
63
overall: 91%
0.0001 —
63
overall: 97%
BCR-ABL1 >0.1-1% BCR-ABL1 >1%-10%
26 19
74% 70%
.011 .0041
27 22
85% 96%
.039 .18
BCR-ABL1 >10%
41
56% overall:
<0001 0.0001
50
80% overall:
.0020 0.012
6 mo BCR-ABL1 0.1% BCR-ABL1 >0.1-1% BCR-ABL1 >1%-10% BCR-ABL1 >10% 12 mo BCR-ABL1 0.1%
<0001 <0001
*p -value —
.33 .0076 0.029 —
*Calculated across the entire post-landmark timespan and unadjusted for multiple comparisons
CML-107 Dropled Digital PCR May Have a Prognostic Value for Predicting Relapse after Imatinib Discontinuation Carmen Fava ,1 Marta Varotto,2 Paola Berchialla,1 Enrico Gottardi,1 Filomena Daraio,1 Roberta Lorenzatti,1 Emilia Giugliano,1 Davide Barberio,2 Alessandra Iurlo,3 Ester Orlandi,4 Patrizia Pregno,5 Dario Ferrero,6 Giovanna Rege-Cambrin,1 Giuseppe Saglio1 1
Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Orbassano, Italy; 2Bioclarma SRL, Torino, Italy; 3UOC Oncoematologia, Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico, Milano, Italy; 4Dipartimento di Onco-Ematologia, Unità di Ematologia Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 5
S.C. Ematologia, Dip. di Oncologia ed Ematologia, A.O. Città della
Salute e della Scienza di Torino, Torino, Italy; 6Divisione Di Ematologia Dell’ Università Degli Studi Di Torino, Città Della Salute E Della Scienza Di Torino, Torino, Italy
Context: Nowadays it is possible to safely discontinue imatinib but it is still not clear which patient (pt) will relapse. High sensitivity techniques like droplet digital (dd) PCR may help to discriminate pts who still present a significant amount of disease despite being in MR4 by standard RT-PCR. Objective: To evaluate the capability of ddPCR to predict relapse after imatinib discontinuation in CML pts with stable MR4 by RQ-
S62
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Clinical Lymphoma, Myeloma & Leukemia September 2016
PCR. Patients and Main Outcome Measures: Total RNA was extracted at different time-points from 19 patients in stable MR4 (i.e. at least 2 years) along one year before discontinuation of imatinib. ddPCR was carried out in triplicate using 200 ng of cDNA for each replicates and droplets were analyzed by QX100Ô droplet reader (Bio-Rad). All results were expressed as BCR-ABL1 /ABL1%. Main Outcome Measures: The Agreement Coefficient of the 2 methods was calculated with Cohen’s K test, Logistic Regression was used to assess the relationship between the probability of relapse and disease level by RT-PCR and ddPCR. Results: A total of 48 samples were retrospectively analyzed by RT-qPCR and ddPCR. All patients discontinued imatinib; 8 had to restart treatment for loss of MMR after a median of 5.3 months (2.2-8.5). 16 patients had >2 evaluations (Table 1). Over one year of molecular follow-up before discontinuation, for negative values obtained measuring BCR-ABL1 by RT-qPCR the probability of a relapse was 45%. On the contrary the probability of a relapse for negative values of BCR-ABL1 by ddPCR was about 30% and it grew linearly at increasing levels of transcript, achieving a probability of about 69% at BCR-ABL1/ABL1% equal to 0.008% (Figure 1). The difference between RT-qPCR and ddPCR in predicting relapse was statistically significant (p 0.02). Conclusions: Our results confirmed that the ddPCR is more sensitive than RT-PCR for low levels of disease and molecular determination by ddPCR at several time-points before discontinuation may have a prognostic value for predicting relapse.
Abstracts Table 1 Agreement of results by RT-qPCR and ddPCR RT-PCR > 0 [Pts]
ddPCR > 0 [Pts]
-3
1/15 (7%)
4/15 (27%)
0/15 (0%)
-0.11 (no agreement)
0.043
-6 -9
3/14 (21%) 3/10 (30%)
8/14 (57%) 9/10 (90%)
3/14 (21%) 3/10 (30%)
0.57 (moderate agreement) 0.09 (slight agreement)
0.13 0.34
-12
1/6 (17%)
2/6 (33%)
1/6 (17%)
0.34 (fair agreement)
0.08
Time-Points (months)
Figure 1 Relationship between BCR-ABL1/ABL1 % and Probability of Relapse by Methods
CML-124 Rapid Achievement of MR4.5 after Switching from Imatinib to Nilotinib in Patients with Chronic Myeloid Leukemia in Chronic Phase (CMLCP): Preliminary Results from ENESTgoal Ellen Ritchie ,1 Michael Deininger,2 Harry Erba,3 Michael Savona,4 Carole Paley,5 Ilva Dautaj,5 Michael Mauro6
Positive with Both Agreement Coefficient Methods (Kappa’s Cohen)
P-Value
patients who achieve MR4.5 within 2 years of switching to nilotinib (monitoring phase) and maintain MR4.5 during a subsequent 2-year nilotinib (consolidation phase) are then eligible to attempt TFR. During TFR phase, patients with loss of MMR are required to reinitiate nilotinib. The primary endpoint is molecular relapse-free rate 6 months after attempting TFR. An analysis of data collected on nilotinib in the monitoring/consolidation phases is presented here. Results: Fifty-nine patients were enrolled by January 9, 2015 (median age, 54 years). Baseline Sokal risk scores in patients were high (9%), intermediate (15%), low (56%), and unknown (20%). Median duration of prior imatinib was 64 months. As of October 2, 2015, 46 patients (78%) were on study (monitoring phase, n¼17; consolidation phase, n¼26; TFR phase, n¼1), and 13 patients (22%) had discontinued (monitoring phase, n¼10; consolidation phase, n¼3). Most common reasons for study discontinuation included AEs/abnormal laboratory finding (n¼5) or withdrawn consent (n¼4). Median nilotinib exposure was 15.9 months (range, 0.2-24.2 months). Majority of AEs were of low grade. Most common grade 3/4 AEs were elevated lipase (10%), headache (2%), and rash (2%). Nilotinib-related AEs (10%; all-grade) included rash (24%), fatigue (20%), pruritus (17%), lipase increase (14%), constipation (14%), abdominal pain (12%), headache (12%), and nausea (10%). There were no QTcF values >500 ms and no deaths. Among 32 patients (54%) who achieved confirmed MR4.5 by data cutoff, the median time to and duration of first confirmed MR4.5 was 204 days (range, 57-638 days) and 90 days (range, 29514 days), respectively. After 1 year, 3 patients entered TFR phase of consolidation (1 remains in TFR). Conclusion: After switching from imatinib to nilotinib, 54% of patients achieved confirmed MR4.5 with a median treatment duration of 17.3 months. Safety results were consistent with the previous studies.
1
Division of Hematology Oncology Weill Cornell Medical College, New
York City, NY, United States; 2The University of Utah, Salt Lake City, UT, United States; 3University of Alabama at Birmingham and UAB Comprehensive Cancer Center, Birmingham, AL, United States; 4
Vanderbilt University Medical Center, Nashville, TN, United States;
5
Novartis Pharmaceuticals Corporation, East Hanover, NJ, United
States; 6Memorial Sloan Kettering Cancer Center, New York City, NY, United States
Background: ENESTgoal is an ongoing phase 2 study of treatment-free remission (TFR) after second-line nilotinib in patients who achieved major molecular response (MMR) but not MR4.5 on imatinib. Methods: Adult patients with Ph+ CML-CP who achieved MMR but not MR4.5 after 1 year of imatinib therapy were switched to nilotinib 300 mg BID upon enrollment. On study,
CML-141 Inhibition of B-Catenin and Bcr-Abl Tyrosine Kinase Synergistically Targets Blast Crisis CML Cells and Stem/ Progenitor Cells In Vitro and In Vivo
Bing Carter ,1 Hongsheng Zhou,1,2 Po Mak,1 Hong Mu,1 Duncan Mak,1 Zhihong Zeng,1 Jorge Cortes,1 Michael Andreeff1 1
Section of Molecular Hematology and Therapy, Department of
Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; 2Department of Hematology, Nanfang
Clinical Lymphoma, Myeloma & Leukemia September 2016
- S63
n
PFS
*p -value
n
OS
3 mo BCR-ABL1 0.1%
32
97%
—
33
97%
BCR-ABL1 >0.1-1% BCR-ABL1 >1%-10%
47 51
70% 61%
.39 .0080
48 55
85% 81%
.60 .13
BCR-ABL1 >10%
82
54% overall:
.0003 0.0013
94
78% overall:
.16 0.34
58 42
91% 60%
— .0023
61 44
93% 83%
— .036
30 57
61% 53%
32 74
90% 78%
63
overall: 91%
0.0001 —
63
overall: 97%
BCR-ABL1 >0.1-1% BCR-ABL1 >1%-10%
26 19
74% 70%
.011 .0041
27 22
85% 96%
.039 .18
BCR-ABL1 >10%
41
56% overall:
<0001 0.0001
50
80% overall:
.0020 0.012
6 mo BCR-ABL1 0.1% BCR-ABL1 >0.1-1% BCR-ABL1 >1%-10% BCR-ABL1 >10% 12 mo BCR-ABL1 0.1%
<0001 <0001
*p -value —
.33 .0076 0.029 —
*Calculated across the entire post-landmark timespan and unadjusted for multiple comparisons
CML-107 Dropled Digital PCR May Have a Prognostic Value for Predicting Relapse after Imatinib Discontinuation Carmen Fava ,1 Marta Varotto,2 Paola Berchialla,1 Enrico Gottardi,1 Filomena Daraio,1 Roberta Lorenzatti,1 Emilia Giugliano,1 Davide Barberio,2 Alessandra Iurlo,3 Ester Orlandi,4 Patrizia Pregno,5 Dario Ferrero,6 Giovanna Rege-Cambrin,1 Giuseppe Saglio1 1
Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Orbassano, Italy; 2Bioclarma SRL, Torino, Italy; 3UOC Oncoematologia, Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico, Milano, Italy; 4Dipartimento di Onco-Ematologia, Unità di Ematologia Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 5
S.C. Ematologia, Dip. di Oncologia ed Ematologia, A.O. Città della
Salute e della Scienza di Torino, Torino, Italy; 6Divisione Di Ematologia Dell’ Università Degli Studi Di Torino, Città Della Salute E Della Scienza Di Torino, Torino, Italy
Context: Nowadays it is possible to safely discontinue imatinib but it is still not clear which patient (pt) will relapse. High sensitivity techniques like droplet digital (dd) PCR may help to discriminate pts who still present a significant amount of disease despite being in MR4 by standard RT-PCR. Objective: To evaluate the capability of ddPCR to predict relapse after imatinib discontinuation in CML pts with stable MR4 by RQ-
S62
-
Clinical Lymphoma, Myeloma & Leukemia September 2016
PCR. Patients and Main Outcome Measures: Total RNA was extracted at different time-points from 19 patients in stable MR4 (i.e. at least 2 years) along one year before discontinuation of imatinib. ddPCR was carried out in triplicate using 200 ng of cDNA for each replicates and droplets were analyzed by QX100Ô droplet reader (Bio-Rad). All results were expressed as BCR-ABL1 /ABL1%. Main Outcome Measures: The Agreement Coefficient of the 2 methods was calculated with Cohen’s K test, Logistic Regression was used to assess the relationship between the probability of relapse and disease level by RT-PCR and ddPCR. Results: A total of 48 samples were retrospectively analyzed by RT-qPCR and ddPCR. All patients discontinued imatinib; 8 had to restart treatment for loss of MMR after a median of 5.3 months (2.2-8.5). 16 patients had >2 evaluations (Table 1). Over one year of molecular follow-up before discontinuation, for negative values obtained measuring BCR-ABL1 by RT-qPCR the probability of a relapse was 45%. On the contrary the probability of a relapse for negative values of BCR-ABL1 by ddPCR was about 30% and it grew linearly at increasing levels of transcript, achieving a probability of about 69% at BCR-ABL1/ABL1% equal to 0.008% (Figure 1). The difference between RT-qPCR and ddPCR in predicting relapse was statistically significant (p 0.02). Conclusions: Our results confirmed that the ddPCR is more sensitive than RT-PCR for low levels of disease and molecular determination by ddPCR at several time-points before discontinuation may have a prognostic value for predicting relapse.
Abstracts Table 1 Agreement of results by RT-qPCR and ddPCR RT-PCR > 0 [Pts]
ddPCR > 0 [Pts]
-3
1/15 (7%)
4/15 (27%)
0/15 (0%)
-0.11 (no agreement)
0.043
-6 -9
3/14 (21%) 3/10 (30%)
8/14 (57%) 9/10 (90%)
3/14 (21%) 3/10 (30%)
0.57 (moderate agreement) 0.09 (slight agreement)
0.13 0.34
-12
1/6 (17%)
2/6 (33%)
1/6 (17%)
0.34 (fair agreement)
0.08
Time-Points (months)
Figure 1 Relationship between BCR-ABL1/ABL1 % and Probability of Relapse by Methods
CML-124 Rapid Achievement of MR4.5 after Switching from Imatinib to Nilotinib in Patients with Chronic Myeloid Leukemia in Chronic Phase (CMLCP): Preliminary Results from ENESTgoal Ellen Ritchie ,1 Michael Deininger,2 Harry Erba,3 Michael Savona,4 Carole Paley,5 Ilva Dautaj,5 Michael Mauro6
Positive with Both Agreement Coefficient Methods (Kappa’s Cohen)
P-Value
patients who achieve MR4.5 within 2 years of switching to nilotinib (monitoring phase) and maintain MR4.5 during a subsequent 2-year nilotinib (consolidation phase) are then eligible to attempt TFR. During TFR phase, patients with loss of MMR are required to reinitiate nilotinib. The primary endpoint is molecular relapse-free rate 6 months after attempting TFR. An analysis of data collected on nilotinib in the monitoring/consolidation phases is presented here. Results: Fifty-nine patients were enrolled by January 9, 2015 (median age, 54 years). Baseline Sokal risk scores in patients were high (9%), intermediate (15%), low (56%), and unknown (20%). Median duration of prior imatinib was 64 months. As of October 2, 2015, 46 patients (78%) were on study (monitoring phase, n¼17; consolidation phase, n¼26; TFR phase, n¼1), and 13 patients (22%) had discontinued (monitoring phase, n¼10; consolidation phase, n¼3). Most common reasons for study discontinuation included AEs/abnormal laboratory finding (n¼5) or withdrawn consent (n¼4). Median nilotinib exposure was 15.9 months (range, 0.2-24.2 months). Majority of AEs were of low grade. Most common grade 3/4 AEs were elevated lipase (10%), headache (2%), and rash (2%). Nilotinib-related AEs (10%; all-grade) included rash (24%), fatigue (20%), pruritus (17%), lipase increase (14%), constipation (14%), abdominal pain (12%), headache (12%), and nausea (10%). There were no QTcF values >500 ms and no deaths. Among 32 patients (54%) who achieved confirmed MR4.5 by data cutoff, the median time to and duration of first confirmed MR4.5 was 204 days (range, 57-638 days) and 90 days (range, 29514 days), respectively. After 1 year, 3 patients entered TFR phase of consolidation (1 remains in TFR). Conclusion: After switching from imatinib to nilotinib, 54% of patients achieved confirmed MR4.5 with a median treatment duration of 17.3 months. Safety results were consistent with the previous studies.
1
Division of Hematology Oncology Weill Cornell Medical College, New
York City, NY, United States; 2The University of Utah, Salt Lake City, UT, United States; 3University of Alabama at Birmingham and UAB Comprehensive Cancer Center, Birmingham, AL, United States; 4
Vanderbilt University Medical Center, Nashville, TN, United States;
5
Novartis Pharmaceuticals Corporation, East Hanover, NJ, United
States; 6Memorial Sloan Kettering Cancer Center, New York City, NY, United States
Background: ENESTgoal is an ongoing phase 2 study of treatment-free remission (TFR) after second-line nilotinib in patients who achieved major molecular response (MMR) but not MR4.5 on imatinib. Methods: Adult patients with Ph+ CML-CP who achieved MMR but not MR4.5 after 1 year of imatinib therapy were switched to nilotinib 300 mg BID upon enrollment. On study,
CML-141 Inhibition of B-Catenin and Bcr-Abl Tyrosine Kinase Synergistically Targets Blast Crisis CML Cells and Stem/ Progenitor Cells In Vitro and In Vivo
Bing Carter ,1 Hongsheng Zhou,1,2 Po Mak,1 Hong Mu,1 Duncan Mak,1 Zhihong Zeng,1 Jorge Cortes,1 Michael Andreeff1 1
Section of Molecular Hematology and Therapy, Department of
Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; 2Department of Hematology, Nanfang
Clinical Lymphoma, Myeloma & Leukemia September 2016
- S63