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2873 Toxicities Associated with Tyrosine Kinase Inhibitor Maintenance Following Allogeneic Hematopoietic Cell Transplantation in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Clinical Research, Diseases, real-world evidence, Therapies, Lymphoid Malignancies, Adverse Events
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Tamer Othman, MD1, Paul B. Koller, MD2, NI-Chun Tsai, MS3*, Dat Ngo, PharmD4*, Jason Chen5*, Amanda Blackmon, DO, MS2*, Hoda Pourhassan, MD6, Vaibhav Agrawal, M.D.2, Idoroenyi Amanam, MD7, Brian J. Ball, MD2, Salman Otoukesh, MD2, Amandeep Salhotra, MD8, Shukaib Arslan, MD2, Monzr M. Al Malki, MD8, Haris Ali, MD2, Karamjeet S. Sandhu, MD2, Ahmed Aribi, MD2*, Andrew Artz, MD, MS9, Forest Marc Stewart, MD2, Eileen Patricia Smith, MD2, Anthony Stein, MD2, Guido Marcucci, MD2, Ryotaro Nakamura, MD10, Vinod Pullarkat, MD2, Ibrahim Aldoss, MD2 and Matthew Genyeh Mei, MD9*

1City of Hope, San Lorenzo, CA
2Hematology/HCT, City of Hope National Medical Center, Duarte, CA
3Computational and Quantitative Medicine, City of Hope National Medical Center, Duarte, CA
4Pharmacy, City of Hope National Medical Center, DUARTE, CA
5Pharmacy, City of Hope, Duarte, CA
6Hematology/HCT, City of Hope, Duarte, CA
7Department of Hematologic Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA
8Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
9City of Hope, Duarte, CA
10Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Comprehensive Cancer Center, Duarte, CA


Use of tyrosine kinase inhibitor (TKI) maintenance following allogeneic hematopoietic cell transplantation (HCT) in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia may help to prevent post HCT relapse but is difficult to administer due to toxicity. However, these toxicities and their impact on maintenance is not fully characterized. Herein, we report our experience at a single, large transplant center to describe toxicities encountered with post HCT TKI maintenance in Ph+ ALL.


Ph+ ALL patients (pts) who underwent 1st allogeneic HCT at City of Hope between 2003-2021 and received at least one dose of TKI maintenance were included in this retrospective analysis. Baseline characteristics and toxicities were summarized via descriptive analysis, and groups were compared via Fischer test. Survival analyses were calculated from the time of TKI initiation.


Baseline characteristics are described in Table 1. Of the 186 pts studied, 50 (26.8%) received imatinib and 136 (73.2%) received a newer generation TKI (NG-TKI: 112 dasatinib, 6 nilotinib, 1 bosutinib, 17 ponatinib) at a median time of 78 days (IQR, 41-134) and 91 days (IQR, 58-129), respectively. A total of 96 patients (51.6%) began TKI maintenance within 90 days of HCT. Post HCT TKI was started prophylactically in 149 patients (80.1%) while 37 patients (19.9%) received TKI preemptively for positive MRD. The MRD status at time of HCT differed between the imatinib group and NG-TKI group. In the imatinib group MRD was negative in 33 of 50 patients (66.0%) compared with 78 of 136 patients (57.4%) in the NG-TKI group (P<0.01). There were 12 (24.0%) vs 18 (13.2%) with an unknown MRD-status at HCT in the imatinib vs NG-TKI groups, respectively (P<0.01). The median follow-up duration for surviving patients in the entire cohort was 5.5 years (range, 1.0-17.5). The median cumulative TKI exposure was 413.5 days (range, 4-2740).

The median cumulative imatinib exposure in patients initially receiving imatinib was 328 days (range, 3-2216), while the median cumulative NG-TKI exposure in patients initially receiving NG-TKI was 268.5 days (range, 3-2740), respectively. The median cumulative exposure of dasatinib, nilotinib, bosutinib and ponatinib were 249 days (range, 3-2740), 222 days (range, 114-839), 371 days, and 576 days (range, 72-921), respectively. Twenty-seven (54.0%) vs 75 (55.2%) patients completed >12 months of initial imatinib and NG-TKI maintenance (P=1.0), respectively.

Of the treated patients, 78 pts (41.9%) required at least one dose reduction of their initial TKI due to toxicity; 19 of them (10.2%) required ≥2 dose reductions. When imatinib maintenance was used as the initial TKI, a dose reduction due to toxicity was required in 18 patients (36.0%), of whom 7 patients (14.0%) required ≥2 dose reductions. Initial NG-TKI maintenance required a dose reduction due to toxicity in 60 (44.1%), of whom 12 (8.8%) required ≥2 dose reductions. One hundred and thirty-nine patients (74.7%) had their maintenance TKI therapy interrupted, 122 (65.6%) due to toxicity. Sixty-seven patients (36.0%) did not complete their pre-determined maintenance period owing to toxicity; 70 pts (37.6%) discontinued one TKI, and 11 (5.9%) discontinued two TKIs, due to toxicity. The most common reasons for discontinuing the initial TKI are listed in Table 2, including 45.2% of patients due to toxicity, and 12.9% due to progressive disease. Toxicity-related discontinuations occurred within 6 months on that TKI in 63.0% of patients, and 75.3% within the first 12 months. Five-year overall survival and progression-free survival from the start of TKI were similar between the imatinib and NG-TKI group; 83.1% vs 76.9% (P=0.74) and 72.8% vs 70.5% (P=0.63), respectively (Figure 1).


Toxicities resulting in dose reductions, interruptions, and discontinuation are common in TKI maintenance post HCT. The toxicity profile (mainly GI and blood count related), frequency, and severity of TKIs in the post HCT setting appears to be different than what has been previously reported in the pre-HCT setting, making it a formidable challenge to meet the recommended cumulative TKI maintenance exposure (2 years) per the NCCN guidelines. While the choice of TKI did not appear to impact on long-term outcomes and relapse rates were not excessive in our analysis, further studies are needed to develop tolerable and personalized TKI maintenance strategies.

Disclosures: Koller: treadwell therapuetics: Consultancy, Other: safety review committee; takeda: Consultancy, Speakers Bureau; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salhotra: BMS: Research Funding; OrcaBio: Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees; Sanofi: Speakers Bureau; Rigel Pharma: Research Funding; Jazz Pharma: Research Funding; Kura Oncology: Research Funding; Gilead: Research Funding. Al Malki: Tscan: Consultancy. Ali: Karyopharm: Consultancy; GSK: Consultancy; Pharmaessentia: Consultancy; Blueprints: Speakers Bureau; BMS: Speakers Bureau; Incyte: Research Funding. Sandhu: Autolus Therapeutics: Consultancy; City of Hope Medical Center: Current Employment. Aribi: Kite, a Gilead Company: Consultancy; Seagen: Consultancy. Artz: Radiology Partner: Current equity holder in private company, Other: Spouse equity interest; Astra Zeneca: Other: Advisory Board; Magenta Therapeutics: Other: Advisory Board; Abbvie: Consultancy. Stein: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Marcucci: Ostentus Therapeutics: Current equity holder in private company, Research Funding. Nakamura: Leukemia & Lymphoma Society: Other: grant reviewer; International Consortium: Other: consortium chair; NCCN: Other: guideline panel for HCT; Blue Bird: Consultancy; Napajen: Consultancy; NCTN Lymphoma Steering Committee: Membership on an entity's Board of Directors or advisory committees; Mt. Sinai: Other: Acute GVHD; Omeros: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: research collaboration; Miyarisan: Research Funding; BMT CTN Steering Committee: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy. Pullarkat: Genentech: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Aldoss: KiTE: Consultancy; Sobi: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria; Takeda: Consultancy. Mei: Incyte: Research Funding, Speakers Bureau; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; SeaGen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA: Membership on an entity's Board of Directors or advisory committees; Beigene: Research Funding; BMS: Research Funding.

OffLabel Disclosure: Bosutinib and nilotinib are not approved for the treatment of Ph+ ALL.

*signifies non-member of ASH