Toxicities Associated with Tyrosine Kinase Inhibitor Maintenance Following Allogeneic Hematopoietic Cell Transplantation in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Authors: Othman Tamer , Koller Paul B. , Tsai NI-Chun , Ngo Dat , Chen Jason , Blackmon Amanda , Pourhassan Hoda , Agrawal Vaibhav , Amanam Idoroenyi , Ball Brian J. , Otoukesh Salman , Salhotra Amandeep , Arslan Shukaib , Al Malki Monzr M. , Ali Haris , Sandhu Karamjeet S. , Aribi Ahmed , Artz Andrew , Stewart Forest Marc , Smith Eileen Patricia , Stein Anthony , Marcucci Guido , Nakamura Ryotaro , Pullarkat Vinod , Aldoss Ibrahim , Mei Matthew Genyeh 
Published: December 2023

Background

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.

Methods

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.

Results

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&lt;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&lt;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 &gt;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).

Conclusion

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.