-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

2695 Dynamic Personalized Assessment of Outcome in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Poster II
Hematology Disease Topics & Pathways:
Diseases, Leukemia, ALL, Biological, Adult, Therapies, Study Population, Lymphoid Malignancies, Clinically relevant, TKI, stem cells
Sunday, December 2, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Koji Sasaki, MD1, Elias J. Jabbour, MD1, Farhad Ravandi, MBBS1, Nicholas J Short, MD1, Guillermo Garcia-Manero, MD2, Naval G. Daver, MD1, Tapan M. Kadia, MD3, Marina Y. Konopleva, MD, PhD1, Nitin Jain, MD4, Ghayas C. Issa, MD1*, Victoria Jeanis, RN5*, Joie Alvarez, RN1*, Maria Khouri1*, Patrice Nasnas, MD1*, Rebecca E. Garris, MSc1*, William G. Wierda, MD, PhD2, Philip A. Thompson, MBBS1, Naveen Pemmaraju, MD1, Jorge E. Cortes, MD1, Susan M. O'Brien, MD6 and Hagop M. Kantarjian, MD2

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX
3Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX
4Department of Leukemia, MD Anderson Cancer Center, Houston, TX
5Deaprtment of Leukemia, The University of Texas MD Anderson Cancer Center, Hosuton, TX
6UC Irvine, Chao Family Comprehensive Cancer Center, Orange, CA

Introduction

The combination of tyrosine kinase inhibitors (TKI) with intensive therapy has improved survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The survival with the combination of hyper-CVAD (HCVAD) with ponatinib has now reached 3-year overall survival of 75%. Allogeneic stem cell transplant (ASCT) is indicated for patients with Ph+ALL in first complete response (CR) as standard recommendation. Given observed improved survival with effective frontline therapy and the risk of treatment-related mortality associated with ASCT, personalized assessment of the indication of ASCT is needed with the consideration of longitudinal data of BCR-ABL1 transcript levels after therapy. Conventional statistical models cannot incorporate dependencies between longitudinal and time-to-event data. Therefore, joint models can combine these two types of data to assess the effect of treatment as well as the impact of longitudinal biomarkers such as BCR-ABL1 transcript levels. The aim of this study is to develop a multivariate joint model for dynamic personalized assessment of outcome in patients with Ph+ALL with or without ASCT.

Methods

From April 2001 to June 2017, 223 patients enrolled in frontline trials of the combination of intensive therapy with TKI were analyzed (HCVAD [hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone] + imatinib, 54 patients; HCVAD + dasatinib, 72 patients; HCMAD [hyper-fractionated cyclophosphamide, liposomal vincristine, doxorubicin, and dexamethasone] + TKI, 21 patients; HCVAD + ponatinib, 68 patients), including 2445 measurements of BCR-ABL1 transcripts by reverse transcriptase polymerase chain reaction. Multivariate joint modeling with multiple longitudinal measurements was performed for dynamic personalized assessment with the combination of multivariate Cox proportional hazard model with generalized linear mixed models. For the estimation of parameters of the joint model, a Bayesian approach was used with Markov Chain Monte Carlo methods. The BCR-ABL1/ABL1 ratio and time from diagnosis to ASCT were considered as time-dependent covariates in the generalized linear mixed model.

Results

Overall, the median follow-up was 72 months (range, 0.2-199.4); HCVAD + imatinib, 168 months; HCVAD + dasatinib, 97 months; HCVAD + ponatinib, 45 months; H (Table 1). The median overall survival (OS) duration was 27.7 months, 67.0 months, not reached, not reached, and 87.2 months in the HCVAD + imatinib, HCVAD + dasatinib, HCVAD + ponatinib, and HCMAD + TKI, respectively (p= 0.027). Of the 48 patients (22%) who received ASCT, the median time to SCT was 5 months (range, 0.89-21.26). The trajectories of BCR-ABL1 transcript levels of P190 and P210 were shown in Figure 1 and Figure 2, respectively. Multivariate joint model identified age at the start of therapy (p <0.001; post-mean, 0.0167; 95% credible interval [CI], 0.0150 – 0.0175), type of transcript (P210 or P190) (p=0.030; post-mean, 2.5375; 95% CI, 1.3568 – 3.9252), BCR-ABL1 transcripts levels at diagnosis (p< 0.001; post-mean, 0.0083; 95% CI, 0.0072 – 0.0097), TKI therapy (imatinib, dasatinib, or ponatinib) (p <0.001; post-mean, -0.4929; 95% CI, -0.5543 – -0.4532), time-dependent logarithmic P190 levels (p= 0.006; post-mean, 0.0407; 95% CI, 0.0300 – 0.0605), time-dependent logarithmic P210 levels (p<0.001; post-mean, 0.0599; 95% CI, 0.0423 – 0.0812), and the use of ASCT (p= 0.020; post-mean, 0.1276; 95% CI, 0.0869 – 0.2371) as prognostic factors for OS. An example of dynamic personalized assessment for the guidance of the ASCT indication was shown in Figure 3. Patient #1 was a 47-year-old male with newly diagnosed Ph+ALL who was treated with front-line HCVAD + ponatinib. At diagnosis, the patient had P190 transcript type with a BCR-ABL level of 100% by reverse transcriptase polymerase chain reaction. At 2.89 months of therapy, his BCR-ABL level was undetectable. Dynamic personalized assessment by multivariate joint model estimated 5-year OS rates were 84.6% (95% CI, 69.4-94.1) without ASCT, and 81.9% (95% CI, 49.8-93.4) with ASCT.

Conclusion

Dynamic personalized assessment of outcome in patients with Ph+ALL is feasible to optimize treatment decision in patients with Ph+ALL. Through the personalized recommendation, the assessment can identify patients who may benefit from ASCT.

Disclosures: Sasaki: Otsuka Pharmaceutical: Honoraria. Jabbour: Abbvie: Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Research Funding. Ravandi: Orsenix: Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Xencor: Research Funding; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria. Short: Takeda Oncology: Consultancy. Daver: Incyte: Consultancy, Research Funding; Kiromic: Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; ARIAD: Research Funding; Pfizer: Research Funding; Pfizer: Consultancy, Research Funding; Alexion: Consultancy; ImmunoGen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Sunesis: Consultancy; Otsuka: Consultancy; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding. Kadia: Abbvie: Consultancy; BMS: Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Research Funding; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Celgene: Research Funding; Takeda: Consultancy; BMS: Research Funding; Jazz: Consultancy, Research Funding. Konopleva: Stemline Therapeutics: Research Funding. Jain: Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; BMS: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wierda: AbbVie, Inc: Research Funding; Genentech: Research Funding. Thompson: Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pemmaraju: celgene: Consultancy, Honoraria; cellectis: Research Funding; samus: Research Funding; novartis: Research Funding; plexxikon: Research Funding; stemline: Consultancy, Honoraria, Research Funding; Affymetrix: Research Funding; abbvie: Research Funding; daiichi sankyo: Research Funding; SagerStrong Foundation: Research Funding. Cortes: Arog: Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. O'Brien: Pharmacyclics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Amgen: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Sunesis: Consultancy, Research Funding; Kite Pharma: Research Funding; Celgene: Consultancy; Aptose Biosciences Inc.: Consultancy; Regeneron: Research Funding; Astellas: Consultancy; TG Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Alexion: Consultancy. Kantarjian: Pfizer: Honoraria, Research Funding; Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria.

*signifies non-member of ASH